Process for the preparation of quaternary N-alkyl morphinan alkaloid salts

ABSTRACT

An improved process for the N-alkylation of tertiary morphinan alkaloid bases to form the corresponding quaternary morphinan alkaloid derivatives.

FIELD OF THE INVENTION

The present invention generally relates to improved processes for thesynthesis of quaternary N-alkyl salts of morphinan alkaloids such asnaltrexone methobromide.

BACKGROUND OF THE INVENTION

N-methyl quaternary derivatives of morphinan alkaloids such asnaltrexone((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-onesometimes referred to as N-cyclopropylmethyl-noroxymorphone) andnaloxone ((5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-onesometimes referred to as N-allyl-noroxymorphone) have usefulpharmacological properties as potent antagonists of the mu receptor.They bind to peripheral receptors primarily located in thegastrointestinal tract, act as antagonists and effectively mitigate someof the undesirable side effects of opiate therapy such as constipationand nausea. Because of their ionic charge, however, they do not traversethe blood brain barrier into the central nervous system; hence, thecentral activity of opiates responsible for pain relief is not blockedin the presence of these quaternary derivatives.

In U.S. Pat. No. 4,176,186, Goldberg et al. generally describe thepreparation of quaternary derivatives of certain morphinan alkaloids byquaternizing a tertiary N-substituted morphinan alkaloid with amethylating agent such as methyl bromide, methyl iodide or dimethylsulfate. Goldberg et al. disclose that the methylating agent itself maybe used as the solvent or, alternatively, another solvent medium such asmethanol, ethanol, or other alcohols, methylene chloride, chloroformtetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide,acetonitrile, nitromethane or hexamethylphosphoric triamide may be used.Goldberg et al. state that they especially prefer acetone because theproduct precipitates in pure crystalline form during the reaction, andin their Example 5, they dissolve N-cyclopropylmethylnoroxymorphone in amixture consisting of 50 mL of absolute acetone and 0.5 mL ofdimethylformamide and then admix the resulting solution with methylbromide. Methyl bromide was used in excess, greater than six-fold molarexcess relative to the free base, over a period of 3 weeks in a pressurevessel.

In WO 2004/043964, Cantrell et al. disclose a process for the synthesisof naltrexone methobromide. For example, 100 g of naltrexone base wasreacted with methyl bromide (MeBr) in 1-methylpyrrolidinone (NMP) at 61to 65° C. to provide 85 g of a crude naltrexone methobromide inapproximately 60 mol. % yield of approximately 90% pure naltrexonemethobromide (see Example 1). Purification of the crude product wascarried out in three steps to give pure naltrexone methobromide; inaddition, 20% of unreacted naltrexone was disposed of in the wastestreams, a significant loss. While this process constitutes significantprogress in the synthesis of naltrexone methobromide and otherquaternary morphinan alkaloids, a need remains for yet furtherimprovement.

In WO 2006/127899, Doshan et al. disclose a stereoselective synthesis ofthe R-isomer of naltrexone methobromide by quaternization of a3-O-protected-naltrexone with a methylating agent followed by removal ofthe protecting group. N-methylation of tertiary morphinan alkaloids hasbeen shown in a previously published NMR study to be highlystereoselective yielding the R-isomer; (see Funke and de Graaf, J. Chem.Soc., Perkins Trans. II, 1985, 385). In the synthesis disclosed byDoshan et al (Example 2), 3-O-isobutyryl-naltrexone was reacted with a4-fold excess of methyl iodide in a sealed glass pressure vessel in anitrogen atmosphere at 88 to 90° C. for 17 hrs. The vessel was thencooled to ambient temperature and evacuated to remove unreacted methyliodide. The product, 3-O-isobutyryl-methylnaltrexone iodide, a whitesolid, was dissolved in a minimum volume of dichloromethane/methanol(4:1) and purified by silica gel chromatography. The 3-O-protectinggroup was removed by reaction with 48% HBr at 64 to 65° C. for 6.5 hoursand the mixture was concentrated to an oil by rotary evaporation at 22to 25° C. Purification of the crude product was carried out by ionexchange on a bromide column and a solid was isolated from selectedpooled fractions. Serial recrystallization of the solid from methanolyielded a white product (64% yield). Product analysis showed an isomerdistribution of approximately 97% R-isomer and 3% S-isomer. Additionalrecrystallizations and/or chromatography (up to 10 times) were requiredto eliminate the S-isomer. Hence, a need remains for furtherimprovement.

SUMMARY OF THE INVENTION

Among the various aspects of the present invention is an improvedprocess for the preparation and/or recovery of quaternary morphinanalkaloids.

Briefly, therefore, the present invention is directed to a process forthe preparation of a quaternary derivative of a tertiary N-substitutedmorphinan alkaloid, the process comprising: (i) combining a tertiaryN-substituted morphinan alkaloid substrate, or a suspension of atertiary N-substituted morphinan alkaloid substrate in an anhydroussolvent system with an alkylating agent, or a solution of the alkylatingagent in the anhydrous solvent system, to form a reaction productmixture containing the quaternary derivative of the tertiaryN-substituted morphinan alkaloid substrate and any unreacted tertiaryN-substituted morphinan alkaloid substrate, the solvent systemcomprising an anhydrous aprotic dipolar solvent(s) with the aproticdipolar solvent(s) constituting at least 25 wt. % of the solvent system;and (ii) adding a non-solubilizing solvent to the reaction productmixture to precipitate the quaternary derivative.

The present invention is further directed to a process for thepreparation of a quaternary derivative of a tertiary N-substitutedmorphinan alkaloid having a C(3) hydroxy substituent, the processcomprising: (i) combining a tertiary N-substituted morphinan alkaloidsubstrate, or a suspension of a tertiary N-substituted morphinanalkaloid substrate in an anhydrous solvent system with an alkylatingagent, or a solution of the alkylating agent in the anhydrous solventsystem, to form a reaction product mixture containing the quaternaryderivative of the tertiary N-substituted morphinan alkaloid substrateand any unreacted tertiary N-substituted morphinan alkaloid substrate,the solvent system comprising an anhydrous aprotic dipolar solvent withthe aprotic dipolar solvent constituting at least 25 wt. % of thesolvent system, and (ii) adding an acid to the reaction product mixtureto suppress ionization of the C(3) hydroxy substituent and production ofC(3) alkoxy side products.

The present invention is further directed to a process for thepreparation of a quaternary derivative of a tertiary N-substitutedmorphinan alkaloid, the process comprising adding less than 3equivalents of an alkylating agent dissolved in an anhydrous dipolaraprotic solvent to a tertiary N-substituted morphinan alkaloid substratedissolved in an anhydrous solvent system, to form a reaction productmixture containing the quaternary derivative of the tertiaryN-substituted morphinan alkaloid substrate and any unreacted tertiaryN-substituted morphinan alkaloid substrate, the rate of addition of thealkylating agent being less than 0.02 equivalents of alkylating agentper equivalent of substrate per minute. In addition, the solvent systemcomprises an aprotic dipolar solvent with the aprotic dipolar solventconstituting at least 25 wt. % of the solvent system, and wherein thesolution of the alkylating agent is maintained at a temperature belowabout 0° C. and is added to the reaction mixture at a temperature ofbetween about 50° C. and about 85° C. so as to limit O-alkylation toless than 10% and inhibit evaporative loss of alkylating agent.

Further still, the present invention is directed to a process for thepreparation of a quaternary derivative of a tertiary N-substitutedmorphinan alkaloid, the process comprising adding less than 3equivalents of a solution of an alkylating agent dissolved in ananhydrous dipolar aprotic solvent to a tertiary N-substituted morphinanalkaloid substrate dissolved in an anhydrous solvent system, to form areaction product mixture containing the quaternary derivative of thetertiary N-substituted morphinan alkaloid substrate and any unreactedtertiary N-substituted morphinan alkaloid substrate, the rate ofaddition of the alkylating agent being less than 0.02 equivalents ofalkylating agent per equivalent of substrate per minute based upon theconcentration of substrate in the reaction mixture; wherein the solutionof the alkylating agent is maintained at a temperature below about 0° C.and is added to the reaction mixture at a temperature of between about50° C. and about 85° C. so as to inhibit O-alkylation at the C(3)hydroxide to less than 10% and inhibit evaporative loss of alkylatingagent.

Further still, the present invention is directed to a process for thepreparation of a quaternary derivative of a tertiary N-substitutedmorphinan alkaloid having a protected C(3) hydroxy substituent, theprocess comprising (i) combining the C(3)-O-protected tertiaryN-substituted morphinan alkaloid substrate, or a suspension of theC(3)-O-protected tertiary N-substituted morphinan alkaloid substrate inan anhydrous solvent system, with an alkylating agent, or a solution ofthe alkylating agent in the anhydrous solvent system, at a pressure ofless than about 2 atmospheres, to form a reaction product mixturecontaining the quaternary derivative of the C(3)-O-protected tertiaryN-substituted morphinan alkaloid substrate and any unreacted tertiaryC(3)-O-protected N-substituted morphinan alkaloid substrate, the solventsystem comprising an anhydrous aprotic dipolar solvent with the aproticdipolar solvent constituting at least 25 wt. % of the solvent system,and subsequently removing the C(3)-O protecting group.

Further still, the present invention is directed to a process for thepreparation of a quaternary derivative of a tertiary N-substitutedmorphinan alkaloid having a C(3-hydroxy substituent, the processcomprising the steps of (i) generating a C(3)-O-protected tertiarymorphinan alkaloid by reacting a C(3)-OH-morphinan alkaloid with aprotecting agent, PG-L; (ii) isolating the generated C(3)-O-protectedtertiary N-substituted morphinan alkaloid; (iii) combining the isolatedC(3)-O-protected tertiary N-substituted morphinan alkaloid with analkylating agent in an anhydrous solvent system to form a reactionproduct mixture, the reaction product mixture containing aC(3)-O-protected quaternary derivative of the C(3)-O-protected tertiaryN-substituted morphinan alkaloid substrate and any unreactedC(3)-O-protected tertiary N-substituted morphinan alkaloid substrate inthe anhydrous solvent system, the anhydrous solvent system comprising anaprotic dipolar solvent with the aprotic dipolar solvent constituting atleast 25 wt. % of the solvent system; (iv) isolating theC(3)-O-protected quaternary derivative from the reaction productmixture; and (v) removing the protecting group from the isolatedC(3)-O-protected quaternary derivative to yield a quaternary derivativeof a tertiary N-substituted morphinan alkaloid having a C(3)-hydroxysubstituent.

The present invention is also directed to the preparation of aquaternary derivative of a tertiary N-substituted morphinan alkaloidhaving a C(3)-hydroxy substituent, the process comprising:

(i) forming a C(3)-protected hydroxy derivative of the tertiaryN-substituted morphinan alkaloid, comprising:

-   -   (A) treating the tertiary N-substituted morphinan alkaloid with        a protecting group precursor in a biphasic first solvent system        comprising water and a water immiscible solvent to form a first        reaction product mixture comprising the C(3)-protected hydroxy        derivative of the tertiary N-substituted morphinan alkaloid and        the water immiscible solvent in an organic layer, and protecting        group precursor, tertiary N-substituted morphinan alkaloid, and        water in an aqueous layer;    -   (B) separating the organic layer from the aqueous layer;    -   (C) drying the organic layer;    -   (D) treating the dried organic layer produced in step (i)(C)        with additional protecting group precursor to increase the        conversion of tertiary N-substituted morphinan alkaloid to the        C(3)-protected hydroxy derivative;    -   (E) removing water immiscible solvent from the treated organic        layer produced in step (i)(D) to form a concentrate comprising        the C(3)-protected hydroxy derivative; and    -   (F) dissolving the concentrate produced in step (i)(E)        comprising the C(3)-protected hydroxy derivative in an anhydrous        solvent system;

(ii) treating the C(3)-protected hydroxy derivative in the anhydroussolvent system of step (i)(F) with an alkylating agent to form a secondreaction product mixture comprising the quaternary derivative of theC(3)-protected hydroxy derivative, unreacted alkylating agent, and anyunreacted C(3)-protected hydroxy derivative; and

(iii) deprotecting the quaternary derivative of the C(3)-protectedhydroxy derivative to form a third reaction product mixture comprisingthe quaternary derivative of the tertiary N-substituted morphinanalkaloid, the quaternary derivative of the tertiary N-substitutedmorphinan alkaloid having a C(3)-hydroxy substituent.

Further still, the present invention is directed to a compositioncomprising R-naltrexone methobromide, S-naltrexone methobromide, theC(3)-O-methyl derivative of naltrexone methobromide, and naltrexonewherein the composition contains at least 70% (w/w) of R-naltrexonemethobromide, at least 1% (w/w) of S-naltrexone methobromide, but nomore than 0.2% (w/w) of the C(3)-O-methyl derivative of naltrexonemethobromide, based upon the combined weight of the R-naltrexonemethobromide, S-naltrexone methobromide, C(3)-O-methyl derivative ofnaltrexone methobromide, and naltrexone in the composition.

Further still, the present invention is directed to a compositioncomprising R-naltrexone methobromide, S-naltrexone methobromide, theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, andoxymorphone wherein the composition contains at least 70% (w/w) ofS-naltrexone methobromide, at least 1% (w/w) of R-naltrexonemethobromide, but no more than 0.2% (w/w) of theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, basedupon the combined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide, and oxymorphone in the composition.

Other objects and features will be in part apparent and in part pointedout hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Among the various aspects of the present invention is an improvedprocess for the N-alkylation of tertiary morphinan alkaloid bases toform a corresponding quaternary morphinan alkaloid derivative. Ingeneral, the process comprises combining a tertiary N-substitutedmorphinan alkaloid substrate with an alkylating agent in an anhydroussolvent system to form the corresponding quaternary derivative. Incertain embodiments, the tertiary morphinan alkaloid base possesses aC(3) hydroxy group; in such embodiments, advantageously, undesiredC(3)-O-alkylation of this C(3) hydroxy group can be inhibited byincluding an anhydrous acid in the reaction mixture. Alternatively, oradditionally, it has been found that by controlling the rate of additionof the alkylating agent to the reaction mixture, evaporative loss of avolatile alkylating agent such as methyl bromide can be inhibited.Further, the solvent system may alternately or additionally comprisesolvents in which the quaternary derivative has less solubility so as toprecipitate the quaternary product and also improve flowability andsubsequent processing of the product mixture. Still further, theC(3)-hydroxy group may be protected in one or a series of protectionreactions to form the C(3)-protected hydroxy derivative of the tertiarymorphinan starting material. The reaction product mixtures (or portionsthereof) containing the desired compounds and intermediates (e.g., thesolvent/organic layer in a biphasic mixture) may be subjected to variouswash and extraction steps in order to remove impurities and by-products.In various embodiments in which the C(3)-protected hydroxy derivative isformed, the alkylating agent may be purged from the reaction mixtureprior to removal of the C(3)-hydroxy protecting group.

Tertiary Morphinan Alkaloid Bases and Quaternary Products

In one embodiment, the tertiary N-substituted morphinan alkaloidsubstrate has the structure of Formula 1 and the quaternary derivativehas the structure of Formula 1A:

wherein

A is —C(O)—, —C(S)—, —C(═CH₂)—, —CH(A₁)- or —C(A₁)=,

A₁ is hydroxy, alkoxy, or acyloxy,

R¹ is hydrocarbyl or substituted hydrocarbyl,

R² is hydrocarbyl or substituted hydrocarbyl,

X¹ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate,methylsulfate, ethylsulfate, trifluoromethanesulfonate,hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;

Y, if present, is hydrogen, hydroxy, protected hydroxy, alkoxy, oracyloxy,

Z is hydroxy, protected hydroxy, alkoxy, or acyloxy, and the dashedlines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and14, respectively, represent (i) carbon-carbon single bonds, (ii)carbon-carbon single bonds between positions 6 and 7 and betweenpositions 8 and 14, and a double bond between positions 7 and 8, or(iii) conjugated carbon-carbon double bonds between positions 6 and 7and positions 8 and 14, with the proviso that Y is not present if thereis a double bond between the carbons at positions 8 and 14.

In one embodiment, Y and Z are independently protected hydroxycomprising —OCH₃, —OAc, —OTHP, —OSiR₃, —OBn, —OBz, —OBs, —OTs, or —OMswherein each R is independently hydrocarbyl.

As previously mentioned, in certain embodiments, the tertiary morphinanalkaloid base possesses a hydroxy group, more specifically a C(3)hydroxy group when the tertiary morphinan alkaloid base corresponds toFormula 1. In this embodiment, the tertiary N-substituted morphinanalkaloid substrate has the structure of Formula 11 and the quaternaryderivative has the structure of Formula 11A:

wherein A, A₁, R¹, R², X¹, and Y are as defined in connection withFormulae 1 and 1A.

In one embodiment, the tertiary morphinan alkaloid base is representedby Formula 2 and the product is represented by Formula 2A.

wherein

A is —C(O)—, —C(S)—, —C(═CH₂)—, or —CH(A₁)-,

A₁ is hydroxy, alkoxy, or acyloxy,

R¹ is hydrocarbyl or substituted hydrocarbyl,

R² is hydrocarbyl or substituted hydrocarbyl,

X¹ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate,methylsulfate, ethylsulfate, trifluoromethanesulfonate,hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;

Y is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy, and

Z is hydroxy, protected hydroxy, alkoxy, or acyloxy.

Representative tertiary morphinan alkaloids falling within the scope ofFormula 2 include naltrexone((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one),oxymorphone ((5α)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one),oxycodone((5α)-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one),hydromorphone ((5α)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one),naloxone ((5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one),nalmefene((5α)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol)and nalbuphine((5α)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol). Preferredtertiary morphinan alkaloids and quaternary derivatives thereof fallingwithin the scope of Formulae 2 and 2A correspond to Formulae 22 and 22A.

wherein R¹, R², X¹, Y and Z are as defined in connection with Formulae 2and 2A and A₁₀ is oxygen, sulfur or methylene; in one embodiment, A₁₀ ispreferably oxygen or methylene. Tertiary morphinan alkaloids fallingwithin the scope of Formula 22 include naltrexone, oxymorphone,oxycodone, hydromorphone, naloxone, and nalmefene.

Other preferred tertiary morphinan alkaloids and quaternary derivativesthereof falling within the scope of Formulae 2 and 2A correspond toFormulae 222 and 222A.

wherein R¹, R², X¹, Y and Z are as defined in connection with Formulae 2and 2A and A₁ is hydroxy, alkoxy or acyloxy. Tertiary morphinanalkaloids falling within the scope of Formulae 222 include nalbuphine.

In one embodiment, the tertiary morphinan alkaloid base is representedby Formula 3 and the product is represented by Formula 3A.

wherein

A is —C(O)—, —C(S)—, —C(═CH₂)—, or —CH(A₁)-,

A₁ is hydroxy, alkoxy, or acyloxy,

R¹ is hydrocarbyl or substituted hydrocarbyl,

R² is hydrocarbyl or substituted hydrocarbyl,

X¹ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate,methylsulfate, ethylsulfate, trifluoromethanesulfonate,hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;

Y is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy, and

Z is hydroxy, protected hydroxy, alkoxy, or acyloxy.

Representative tertiary morphinan alkaloids falling within the scope ofFormula 3 include morphine((5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol), codeine((5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol),codeinone((5α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-one),14-hydroxy-codeinone((5α)-7,8-didehydro-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one),14-hydroxymorphinone((5α)-7,8-didehydro-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one)and morphinone((5α)-7,8-didehydro-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one).

In another embodiment, the tertiary morphinan alkaloid base isrepresented by Formula 4 and the product is represented by Formula 4A.

wherein

A₁ is hydroxy, alkoxy, or acyloxy,

R¹ is hydrocarbyl or substituted hydrocarbyl,

R² is hydrocarbyl or substituted hydrocarbyl,

X¹ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate,methylsulfate, ethylsulfate, trifluoromethanesulfonate,hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate, and

Z is hydroxy, protected hydroxy, alkoxy, or acyloxy.

Representative tertiary morphinan alkaloids and quaternary derivativesthereof falling within the scope of Formula 4 and Formula 4A,respectively, include thebaine((5α)-6,7,8,14-tetradehydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphinan)and oripavine((5α)-6,7,8,14-tetrahydro-4,5-epoxy-6-methoxy-17-methylmorphinan-3-ol).

In each of these embodiments in which a tertiary alkaloid base isalkylated to form the corresponding N-alkyl quaternary alkaloid saltrepresented by Formula 1A, 2A, 22A, 222A, 3A, or 4A, Z is preferablyhydroxy, protected hydroxy, alkoxy or acyloxy, more preferably hydroxyor methoxy. For example, in each of these embodiments Z may be selectedfrom —OCH₃, —OAc, —OTHP, —OSiR₃ (wherein each R is independentlyhydrocarbyl, preferably lower alkyl), —OBn, —OBz, —OBs, —OTs, or —OMs.By way of further example, in each of these embodiments, Z may behydroxy. In each of these embodiments, Y, if present, is preferablyhydrogen, hydroxy, protected hydroxy, alkoxy or acyloxy, more preferablyhydrogen or hydroxy. For example, in each of these embodiments Y, ifpresent, may be selected from —OCH₃, —OAc, —OTHP, —OSiR₃ (wherein each Ris independently hydrocarbyl, preferably lower alkyl), —OBn, —OBz, —OBs,—OTs, and —OMs. In each of these embodiments, R¹ is preferably methyl,ethyl, propyl, allyl (—CH₂CH═CH₂), chloroallyl, cyclopropylmethyl,cyclobutylmethyl, or propargyl. In each of these embodiments, R² ispreferably alkyl, alkenyl or alkaryl, more preferably lower alkyl, andtypically methyl. In each of these embodiments, X¹ is preferablybromide.

N-Alkylation Reactions

In the process of the present invention, a tertiary N-substitutedmorphinan alkaloid substrate reacts with an alkylating agent in ananhydrous solvent system to form the corresponding quaternaryderivative.

A range of alkylating agents may be used for this purpose. In general,alkylating agents comprising 1 to 8 carbons, optionally substituted andoptionally unsaturated are preferred. Typically, the alkylating agentwill be an alkyl, allyl, alkallyl, propargyl, or benzyl salt of anionssuch as halides or optionally substituted sulfates, sulfonates, borates,phosphates, or antimonates. Thus, for example, the alkylating agent maybe a methyl, ethyl, propyl, allyl, cyclopropyl, cyclopropylmethyl,propargyl or benzyl salt of an anion such as a halide, sulfate,sulfonate, fluorosulfonate, methylsulfate, ethylsulfate,trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, ortetrafluoroborate. Representative examples include methyl bromide,cyclopropylmethyl bromide, dimethyl sulfate, diethyl sulfate,di(cyclopropylmethyl) sulfate, methyl fluorosulfonate, trimethyloxoniumfluoroborate, triethyloxonium fluoroborate, trimethyloxoniumhexachloroantimonate, n-propyl or n-octyl trifluoromethane sulfonate,trimethyloxonium hexafluorophosphate, methyl trifluoromethane sulfonate,and allyl trifluoromethanesulfonate. Amongst the alkyl halides, whilethe chlorides and iodides may be used, the alkyl bromide is generallypreferred as an alkylating agent. Relative to the corresponding alkylbromides, under certain conditions, alkylations with alkyl chloridestend to proceed slowly and alkyl iodides tend to lead to over alkylationof the tertiary alkaloid substrates. In one embodiment, therefore, thealkylating agent is methyl, ethyl, propyl, allyl, cyclopropyl,cyclopropylmethyl, or benzyl bromide. In a typical embodiment, thealkylating agent is methyl bromide or cyclopropylmethylbromide.

In general, an excess of alkylating agent will be employed for thereaction. The alkylating agent may be preformulated as a solution in ananhydrous solvent system (described below) prior to use. As an example,methyl bromide is cooled down to a temperature of about −10° C., and analiquot is added into a vessel containing pre-cooled anhydrous1-Methyl-2-Pyrrolidinone (NMP) also at a temperature of about −10° C. toform a stock solution of the alkylating agent, i.e., methyl bromide inNMP at −10° C. (MeBr/NMP). Large excesses (e.g., more than 3 equivalentsof alkylating agent per equivalent of substrate), however, tend to leadto over-alkylation of the substrate. It is generally preferred,therefore, that the mole ratio of alkylating agent to substrate employedfor the reaction be about 1:1 to 1.5:1, respectively. Further, the rateof addition of the alkylating agent to the reaction mixture can alsohave an effect upon the amount of undesired side-products with theamount of undesired side-products tending to increase as a function ofincreasing rates of addition. Thus, in some instances it may bepreferred that the rate of addition be controlled to minimize thiseffect. For example, in certain embodiments, it is preferred that therate of addition of alkylating agent be less than 0.02 equivalents ofalkylating agent per minute per equivalent of tertiary N-substitutedmorphinan alkaloid substrate in the reaction mixture. In certainembodiments, it is preferred that the rate of addition be even slower;that is, in such embodiments it is preferred that the rate of additionbe less than 0.01 equivalents of alkylating agent per minute perequivalent of tertiary N-substituted morphinan alkaloid substrate in theinitial reaction mixture. In such embodiments, the rate of addition ofalkylating agent will typically be between about 0.002 and 0.02equivalents of alkylating agent per minute per equivalent of tertiaryN-substituted morphinan alkaloid substrate in the reaction mixture.Thus, for example, if the reaction is carried out as a batch process, aninitial reaction mixture is prepared comprising the quantity of tertiaryN-substituted morphinan alkaloid substrate to be converted, andalkylating agent is introduced to the initial reaction mixture at a rateof less than 0.02 equivalents of alkylating agent per minute perequivalent of tertiary N-substituted morphinan alkaloid substrate in theinitial reaction mixture over the period of addition of the alkylatingagent. By way of further example, if the reaction is carried out as acontinuous process (in which substrate and alkylating agent arecontinuously or semi-continuously introduced to the reaction mixture),alkylating agent is introduced to the reaction mixture at a rate of lessthan 0.02 equivalents of alkylating agent per minute per equivalent oftertiary N-substituted morphinan alkaloid substrate in the reactionmixture at the time of addition of the alkylating agent.

The reaction mixture in which the N-alkylation occurs contains a solventsystem (that is, a solvent or mixture of solvents) and is anhydrous. Ina preferred embodiment, the solvent system comprises an aprotic, dipolarsolvent and is anhydrous. More specifically, the solvent systempreferably comprises less than about 0.5 wt. % water, typically lessthan about 0.2 wt. % water, still more typically less than 0.1 wt. %water, and in some embodiments, less than 0.05 wt. % water. In addition,it is preferred that the aprotic, dipolar solvent (or mixture of aproticdipolar solvents) constitute a significant fraction of the solventsystem; for example, in one embodiment the aprotic, dipolar solvent(s)constitute(s) at least about 25 wt. % of the solvent system. Forexample, in some embodiments it is preferred that the aprotic, dipolarsolvent(s) constitute(s) at least about 50 wt. % of the solvent system.In some embodiments, it is preferred that the aprotic, dipolarsolvent(s) constitute(s) at least about 75 wt. % of the solvent system.In a further embodiment, the aprotic, dipolar solvent(s) constitute(s)at least about 90 wt. % of the solvent system. Exemplary aprotic dipolarsolvents include dimethylacetamide, dimethylformamide,N-methylpyrrolidinone, acetonitrile, hexamethylphosphoramide (“HMPA”),and mixtures thereof. In one embodiment, the dipolar aprotic solvent isselected from the group consisting of dimethyl acetamide, dimethylformamide, N-methylpyrrolidinone, HMPA and combinations thereof.N-methylpyrrolidinone (1-methyl-2-pyrrolidinone, NMP) is typicallypreferred, either alone or in combination with another aprotic, dipolarsolvent.

The reaction may be carried out over a wide range of temperatures andpressures. In one embodiment, the reaction will be carried out at atemperature somewhere in the range of room temperature (about 25° C.) toabout 90° C., typically about 55° C. to about 85° C. For example, therate, conversion, yield and concentration of naltrexone base to theN-methylated product in anhydrous 1-methyl-2-pyrrolidinone isadvantageously and dramatically increased at lower reaction temperatures(<70° C.) as compared to the reaction in acetone carried out at 125° C.to 140° C. (>10 atm) over 24 hours.

The N-alkylation reaction may be carried out over a range of pressures.For example, when the alkylating agent is methyl bromide and the methylbromide gas (MeBr) is dissolved in anhydrous 1-methyl-2-pyrrolidinone(NMP), the gas is predominantly retained at temperatures of as high as85° C. at relatively modest elevated pressures (e.g., ≦2 atmospheres)without the need for expensive pressure vessels. In one embodiment,therefore, the N-alkylation reaction is carried out at a pressure not inexcess of 1.5 atmospheres in an aprotic dipolar solvent such as NMP, orin a solvent mixture comprising NMP. Advantageously, for example, theN-alkylation reaction may be carried out at a pressure of 1 to 1.25atmospheres or even at atmospheric pressure.

In accordance with one aspect of the present invention, it has beendetermined that addition of an acid to the reaction mixture tends tosuppress ionization of the phenolic C(3) hydroxy group of a tertiaryN-substituted morphinan alkaloid having a C(3) hydroxy substituent. Theacid is preferably an anhydrous acid. In addition, it is preferably astrong mineral or organic acid. For example, the acid may be acarboxylic acid, a phosphonic acid, a sulfonic acid or a mixturethereof. Alternatively, a small amount of a preformed alkaloid acid saltmay be added to its alkaloid base in order to suppress ionization of thealkaloid base; for example, naltrexone hydrobromide may be added tonaltrexone base. By way of further example, the acid may be HBr, HCl,H₂SO₄, NaHSO₄, NaH₂PO₄, or Na₂HPO₄, containing less than about 0.5 wt. %water, less than 0.2 wt. % water, less than 0.1 wt. % water, or evenless than 0.05 wt. % water. In one embodiment, for example, it ispreferred that the acid be HBr gas, or HCl gas, particularly HBr gas.Conversion rates tend to decrease with increasing acid concentrations.Thus, it is generally preferred that the amount of acid included in thereaction mixture be initially less than 0.25 equivalents of acid perequivalent of substrate. In certain embodiments, it is preferred thatthe amount of acid included in the reaction mixture be about 0.1equivalents of acid per equivalent of substrate. In some embodiments, itmay be preferred that even less acid be employed; for example, in someembodiments it is preferred that the amount of acid be less than 0.10equivalents of acid per equivalent of substrate, less than 0.05equivalents of acid per equivalent of substrate, or even less than 0.01equivalents of acid per equivalent of substrate. In a typical reaction,a stock solution of a strong, anhydrous acid is prepared in theanhydrous solvent and added in aliquots. For example, in a reaction inwhich HBr is the strong anhydrous acid, a sample withdrawn from a sourceof hydrogen bromide (HBO cooled to a temperature of about −70° C. isadded to a sample of 1-methyl-2-pyrrolidinone (N-methylpyrrolidone; NMP)at a temperature of about −20° C. and the solution allowed to warm toroom temperature. The solution may then be further diluted with NMP toform a stock solution of HBr in NMP (HBr/NMP) at a desiredconcentration.

Typically, the substrate for the N-alkylation reactions described herein(e.g., involving substrates containing a C(3) hydroxide) is a dehydratedbase. For example, in reactions utilizing naltrexone, the anhydrous basemay be prepared from naltrexone hydrochloride which has been dried undervacuum until the water content is reduced to about 2% or less byKarl-Fischer analysis. A hydrated base (e.g., naltrexone dihydrate,Naltrexone.2H₂O) may be used in alkylations that involve priorprotection of the phenolic C(3) hydroxide. Further, it has been observedadvantageously that the presence of a strong acid (such as HBr) in thereaction system permits use of partially hydrated naltrexone(Naltrexone.2H₂O) as a starting material instead of anhydrousnaltrexone. Therefore, acidification of the reaction medium affordsreduction in processing costs by eliminating the costs associated withdehydration of naltrexone base prior to alkylation.

In general, relatively concentrated solutions of the substrate arepreferred. That is, the initial reaction mixture preferably comprises nomore than about 2 equivalents of solvent for each equivalent ofN-substituted morphinan alkaloid substrate. In some embodiments, theinitial reaction mixture comprises no more than about 1.75 equivalentsof solvent for each equivalent of N-substituted morphinan alkaloidsubstrate. In other embodiments, the initial reaction mixture comprisesno more than about 1.5 equivalents of solvent for each equivalent ofN-substituted morphinan alkaloid substrate.

In general, the quaternary derivative resulting from the N-alkylation ismore ionic than the N-substituted morphinan alkaloid substrate. As aresult, the quaternary derivative tends to have less solubility innon-polar solvents than the N-substituted morphinan alkaloid substrate.To aid in recovery of the quaternary derivative from the reactionmixture, a solvent (or mixture of solvents) less polar than the aprotic,dipolar solvent(s) may be introduced to the reaction mixture to causethe quaternary derivative to precipitate from solution while leaving theunreacted N-substituted morphinan alkaloid substrate in solution. Suchsolvents, sometimes referred to as non-solubilizing solvents (for thequaternary derivative) are preferably employed in one embodiment of thepresent invention. Typically, the non-solubilizing solvent(s) is(are)introduced to the reaction mixture upon completion of the N-alkylationreaction to cause the quaternary derivative to precipitate from thereaction mixture. Alternatively, however, a fraction of thenon-solubilizing solvent(s) may be added to the reaction mixture priorto, at the initiation of, or during the course of the N-alkylationreaction. In this alternative however, the kinetics of the alkylationmay be adversely affected. Preferably, the quaternary derivative has asolubility of less than 5 wt. % in the non-solubilizing solvent at 1atmosphere and 25° C. In addition, the non-solubilizing solvent ispreferably more miscible with 1-methyl-2-pyrrolidinone than with water;for example, the non-solubilizing solvent preferably has a solubility ofless than about 30 wt. % in water at 1 atmosphere and 25° C. Exemplarynon-solubilizing solvents include chloroform, dichloromethane, ethylacetate, propyl acetate, methyl ethyl ketone, methyl butyl ketone,ether, hydrocarbon, toluene, benzene, chlorobenzene, bromobenzene andmixtures thereof. Of these, chloroform is sometimes preferred.

In general and regardless of synthetic route, N-alkylations of morphinansubstrates that contain a C(3) hydroxy moiety may yield undesirable C(3)alkoxy morphinans. Crude product mixtures containing C(3) hydroxy andC(3) alkoxy morphinans may be purified by adding strong base, e.g.,sodium methoxide, NaOH or KOH in methanol/water, heating the mixture toconvert the C(3) hydroxy morphinan to its oxide salt (e.g., sodiumsalt), adding additional methanol, cooling to precipitate the salt,filtering and drying. Advantageously, the C(3) alkoxy morphinan remainsin solution and does not precipitate along with the salt; as a result,the salt and the C(3) alkoxy morphinan may be readily separated.

The desired N-alkyl morphinan may be regenerated from the salt byredissolving the salt (for example, in a methanol/water solution),adjusting the solution to a low pH (for example, a pH of 0.5 to 1 using45% hydrobromic acid) to regenerate a hydroxy group at the C(3)position, and precipitating the product. In a preferred embodiment, theprecipitated product is recovered by vacuum filtration, washing withadditional methanol and drying to 75° C.

In one embodiment, two or more of the aforementioned preferred steps orfeatures are combined. For example, in one preferred embodiment, theaverage rate of addition of the alkylating agent is controlled (aspreviously described) to minimize over-alkylation of the substrate. Byway of further example, in one embodiment the average rate of additionof the alkylating agent is controlled (as previously described) tominimize over-alkylation of the substrate and a non-solubilizing solventfor the quaternary derivative is added to the reaction mixture to causethe quaternary derivative to precipitate from the reaction mixture whilethe substrate substantially remains dissolved in the solvent system. Byway of further example, in one embodiment the average rate of additionof the alkylating agent is controlled (as previously described) tominimize over-alkylation of the substrate and a strong anhydrous acid(in the amounts previously described) is included in the reactionmixture to inhibit alkylation of the C(3) hydroxy substituent of atertiary N-substituted morphinan alkaloid substrate. By way of furtherexample, in one embodiment the average rate of addition of thealkylating agent is controlled (as previously described) to minimizeover-alkylation of the substrate, a strong anhydrous acid (in theamounts previously described) is included in the reaction mixture toinhibit alkylation of the C(3) hydroxy substituent of a tertiaryN-substituted morphinan alkaloid substrate, and a non-solubilizingsolvent for the quaternary derivative is added to the reaction mixtureto cause the quaternary derivative to precipitate from the reactionmixture while the substrate substantially remains dissolved in thesolvent system. In one preferred embodiment, in each of theseaforementioned combinations, methyl bromide is used as the alkylatingagent, the pressure of the reaction mixture is less than 2 atmospheres(preferably 1 to 1.5 atmospheres), and the temperature of the reactionmixture is not in excess of 80° C.

In one preferred embodiment, the N-alkylation reaction is carried out ata pressure of less than 1.25 atmospheres, the aprotic dipolar solventconstitutes at least 75 wt. % of the solvent system, and the aproticdipolar solvent is 1-methyl-2-pyrrolidinone. In addition, in thispreferred embodiment the anhydrous solvent system contains less than 0.2wt. % water, preferably less than 0.1 wt. % water, more preferably lessthan 0.05 wt. % water, and said anhydrous system is maintained in amoisture-free atmosphere in a reaction vessel. The substrate in thispreferred embodiment corresponds to Formula 1 wherein Y and Z areindependently —OCH₃, —OAc, —OTHP, —OSiR₃, —OBn, —OBz, —OBs, —OTs, or—OMs wherein each R is independently hydrocarbyl. In one particularlypreferred embodiment, the substrate is naltrexone((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one),oxymorphone ((5α)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one),oxycodone((5α)-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one),hydromorphone ((5α)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one),naloxone ((5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one),nalmefene((5α)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol)or nalbuphine((5α)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol).Alternatively, the substrate in this preferred embodiment corresponds toFormula 3 and the substrate is, for example, morphine((5α,6α)-7,8-didehydro-4,5-epoxi-17-methylmorphinan-3,6-diol), codeine((5α,6α)-7,8-didehydro-4,5-epoxi-3-methoxy-17-methylmorphinan-6-ol),codeinone((5α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-one) or14-hydroxy-codeinone((5α)-7,8-didehydro-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one).

Alternate Embodiment for N-Alkylation of C(3)-Hydroxy MorphinanAlkaloids.

N-alkylation of a C(3)-hydroxy morphinan alkaloid substrate (Formula 11)can produce undesired C(3)-alkoxy morphinan side products because of aparallel alkylation of the unprotected C(3)-hydroxy group. This processis exemplified in Scheme 1 below where the undesired side products areC(3)-methoxy morphinan (Formula 11B) and N-alkylated C(3)-methoxymorphinan (Formula 11C) resulting from O-alkylation of the phenolicC(3)-OH, wherein R¹, R², A, X, and Y are as defined in connection withFormulae 1 and 1A.

To inhibit the side reaction (i.e., C(3)-O-alkylation), the phenolicgroup (C(3)-OH) of the tertiary morphinan alkaloid may first beprotected to generate the C(3)-OH-protected tertiary morphinan alkaloid.A single protection reaction may be carried out, or a series ofprotecting reactions may be carried out in order to affect more completeconversion of the C(3)-O-protected derivative from the C(3)-hydroxymorphinan starting material. In one embodiment, a single protection stepis carried out to convert the C(3)-hydroxy morphinan starting materialto the C(3)-protected hydroxy derivative. In another embodiment, twoprotection steps are carried out to convert the C(3)-hydroxy morphinanstarting material to the C(3)-protected hydroxy derivative. In anotherembodiment, three protection steps are carried out to convert theC(3)-hydroxy morphinan starting material to the C(3)-protected hydroxyderivative. In another embodiment, three or more protection steps arecarried out to convert the C(3)-hydroxy morphinan starting material tothe C(3)-protected hydroxy derivative. Regardless of the number ofprotection reactions employed, the protected substrate is thenN-alkylated to yield a protected quaternary morphinan alkaloid. Theprotecting group is subsequently removed to yield the desired quaternarymorphinan alkaloid salt.

Accordingly, in certain embodiments, the tertiary morphinan alkaloidbase possesses a protected C(3)-OH wherein the tertiary N-substitutedmorphinan alkaloid substrate has the structure of Formula 111 and thequaternary derivative has the structure of Formula 111A:

wherein A, A₁, R¹, R², X¹, and Y are as defined in connection withFormulae 1 and 1A; and wherein PG is a hydroxy protecting group. Inthese embodiments, a compound of Formula 111B is produced upon removalof the hydroxy protecting group.

Representative hydroxy protecting groups include optionally substitutedhydrocarbyl, C₁-C₆-alkyl; C₂-C₁₀-alkyloxyalkoxy; C₂-C₆-alkenyl;C₂-C₆-alkynyl; saturated cyclic C₃-C₆-alkyl; C₄-C₁₆-(cyclicalsaturated)alkenyl; C₄-C₁₆-(cyclical saturated)alkynyl; C₇-C₁₆-arylalkyl;C₈-C₁₆-arylalkenyl; C₈-C₁₆-arylalkynyl; C₂-C₆-alkanoyl; C₃-C₆-alkenoyl;C₃-C₆-alkynoyl; C₈-C₁₆-arylalkanoyl; C₉-C₁₆-arylalkenoyl;C₉-C₁₆-arylalkynoyl; sulfonyl or phosphonyl.

A range of hydroxy protecting groups which may be used comprise ethers(alkoxy) and esters (acyloxy); (see T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis (3rd edition), J. Wiley & SonsIn., NY 1999, chapter 3). Common ether protective groups comprisemethyl, methoxymethyl, propargyl, benzyl, trityl, silyl,tris-(C₁-C₆-alkyesilyl or tris-(C₇-C₁₆-arylalkyl)silyl. Common esterprotective groups comprise, formate, acetate, alkyl carbonate, arylcarbonate, aryl carbamate alkylsulfonate, arylsulfonate, triflate,phosphonate or phoshinates. Exemplary hydroxy protecting groups includemethoxymethyl, 1-ethoxyethyl, benzyloxymethyl,(β-trimethylsilylethoxy)methyl, tetrahydropyranyl,2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl,trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

Introduction of a protective group such as benzyl, trityl or silyl tothe C(3)-hydroxy group is achieved by C(3)-O-benzylation,C(3)-O-tritylation or C(3)-O-silylation of the morphinan compounds usingbenzyl halogenides, trityl halogenides, or trialkyl halogen silanes.Such derivatization is effected in a solvent such as toluene,chloroform, chloromethane, chlorobenzene, acetone, dimethyl formamide,or combinations thereof, and in the presence of a base comprising sodiumbicarbonate, potassium carbonate, triethylamine, sodium hydroxide,potassium bicarbonate, or pyridine. Alternately, ester protective groupsmay be introduced in the form of the corresponding acyl halide oranhydride in aqueous media or in dimethyl formamide in the presence of abase such as sodium bicarbonate, sodium hydroxide, potassium carbonate,potassium bicarbonate, pyridine or triethylamine. Further still, thehydroxy protection reaction may be carried out in aqueous-organicsolvent mixtures being combinations of the above listed solvents in thepresence of a base listed above. In one particular embodiment, theprotective group is an acyl moiety, such as an acetyl group, introducedby treatment of the C(3)-hydroxy morphinan with an acyl protecting groupprecursor. Following the hydroxy protection step and the optionalwashing/filtration/solvent exchange steps discussed below, the protectedmorphinan is then quaternized (see Scheme 1).

The C(3)-hydroxy morphinan may be in the free base or salt form;typically, however, the C(3)-hydroxy morphinan is in the free base form.In either case, the morphinan is preferably combined with water and abase (e.g., sodium hydroxide) to assist in the formation of asubstantially homogeneous reaction mixture (e.g., to solubilize thecompound). Typically, the C(3)-hydroxy morphinan starting material iscombined with the water in the reaction vessel prior to the addition ofthe base. Alternatively, however, the water and the base may be combinedand thereafter added to the reaction vessel containing the C(3)-hydroxymorphinan starting material. It will be understood that whereC(3)-hydroxy morphinan salt forms are employed, the amount of water andbase to solubilize the morphinan may vary. For instance, where theC(3)-hydroxy morphinan salt is the hydrochloric acid salt two or moreequivalents of the base may be necessary to completely solubilize thecompound.

After solubilization, the solubilized compound is combined with a waterimmiscible solvent, resulting in the formation of a biphasic solventsystem; the organic layer of the biphasic mixture includes the waterimmiscible solvent (and any water that combined with the solvent in theform of an emulsion), and the aqueous layer of the biphasic mixtureincludes the C(3)-hydroxy morphinan starting material and water.Exemplary water immiscible solvents that may be used include, but arenot limited to, chlorobenzene, chloroform, dichloromethane,1,2-dichloroethane, diethyl ether, ethyl acetate, propyl acetate,tetrahydrofuran, toluene, xylene, combinations thereof, and the like. Ina particular embodiment, the water immiscible solvent is toluene.

In order to affect C(3)-protection of the C(3) hydroxy group, the layersof the biphasic mixture are treated with a protecting group precursor.The protecting group precursor will generally vary depending on theparticular protecting group that is desired for the C(3)-hydroxyposition (as described above). In one embodiment, the protecting groupis an acyl protecting group; more preferably an acetyl protecting group.According to this preferred embodiment, for example, the protectinggroup precursor is typically acetic anhydride. While the discussionherein may focus on the use of acetic anhydride as the protecting groupprecursor in a multi-stage protection protocol, it will be understoodthat other protecting group precursors may be used to introduce aprotecting group to the C(3)-hydroxy position with minor modificationsto conditions that are within the ambit of one of skill in the art.

In a typical C(3)-hydroxy protection reaction involving the introductionof an acetyl group at the C(3)-hydroxy position, for example, thetreatment of the biphasic mixture with acetic anhydride causes theC(3)-protected hydroxy derivative of the C(3)-hydroxy morphinan startingmaterial to precipitate out of the aqueous phase and dissolve into theorganic phase of the biphasic mixture. Thereafter, the organic layerincludes the C(3)-protected hydroxy derivative (the predominant, but notexclusive, morphinan species in the solvent layer), the water immisciblesolvent, and typically a small quantity of the unreacted C(3)-hydroxymorphinan starting material, and the aqueous layer includes anyunreacted or excess protecting group precursor, a majority of theunreacted C(3)-hydroxy morphinan starting material, and water.

In the initial (i.e., first) protection reaction, an excess of theprotecting group precursor (e.g., acetic anhydride) is generallypreferred. In the second, third, and further protection reactions,lesser amounts of protecting group precursor may be employed, as smallerquantities of C(3)-hydroxy morphinan typically remain. As a result ofexcess acetic anhydride in an initial protection reaction, the pH of thebiphasic reaction mixture tends to decrease as a result of the formationof acetic acid which may hydrolyze the C(3)-protected hydroxy derivativeand/or extract the protected derivative from the organic layer into theaqueous layer. Thus, after treatment with the protecting groupprecursor, the pH of the reaction product mixture may be optionallyadjusted to a more basic pH; for example, to a pH of about 9.5 to about10.5, more preferably 10M, with a base such as sodium hydroxide orpotassium hydroxide. In general, adjusting the pH of the protectionreaction mixture can improve downstream yields of the desired products.Thus, in certain embodiments, the pH of the protection reaction mixtureis preferably adjusted (i.e., to a more basic pH) after the protectionreaction and prior to the next process step.

The pH adjustment step, if performed, may cause an undesirablehydrolysis (i.e., removal) of the C(3)-hydroxy protecting group.Additionally or alternatively, unreacted (i.e., unprotected)C(3)-hydroxy tertiary N-unsubstituted morphinan alkaloid may still bepresent in the reaction mixture. Thus, as noted above, it may bedesirable to perform a second C(3)-hydroxy protection reaction, a thirdC(3)-hydroxy protection reaction, or more. For example, the protectionreaction may be carried out once, twice, three times, or more, in orderto protect the C(3)-hydroxy group of any unreacted or hydrolyzedC(3)-hydroxy tertiary N-unsubstituted morphinan alkaloid that remainsafter the initial (or subsequent) protection reactions and/or pHadjustment steps. In one embodiment, the C(3)-hydroxy protectionreaction is repeated at least once. In another embodiment, theC(3)-hydroxy protection reaction is repeated twice; according to thisembodiment, for example, the C(3)-O-protected tertiary morphinanalkaloid substrate is formed after a first protection reaction, andadditional quantities of the C(3)-O-protected tertiary morphinanalkaloid substrate are formed after a second and third protectionreaction.

Each successive protection reaction may be carried out in substantiallythe same manner as the previous protection reaction, and may or may notbe followed by a pH adjustment step as described above. Additionally oralternatively, minor modifications in the protection reaction may bemade. For instance, in one embodiment, the first protection reactiongenerally involves treating the reaction mixture containing C(3)-hydroxytertiary N-unsubstituted morphinan alkaloid with a protecting groupprecursor (e.g., acetic anhydride or other precursor capable ofprotecting the C(3)-hydroxy group with a acyl or acetyl moiety), andsubsequently adjusting the pH of the reaction mixture to about 9.5 toabout 10.5. While additional protection reactions may be carried out ina similar manner, smaller quantities of the protecting group precursorare generally employed in the subsequent (i.e., second and third)protection reactions since lesser quantities of unprotected C(3)-hydroxymorphinan alkaloid are generally present.

Where at least two protection reactions are performed, the resultingC(3)-protected product mixture may be optionally filtered to remove anysediment or other insoluble components or by-products from the mixture.In general, conventional filtration techniques may be employed (e.g.,macro- or micro-filtration). In the embodiments in which threeprotection reactions, or more are employed, the filtration step ispreferably carried out after the second protection reaction.

After the first one or two protection steps have been performed and theresulting mixture is optionally filtered, the biphasic reaction productmixture may be subjected to an aqueous/organic extraction to removeby-products and other impurities. In general, conventionalaqueous/organic extraction techniques may be utilized. In a particularembodiment, additional water immiscible solvent (e.g., toluene) is addedto the biphasic mixture containing the C(3)-protected hydroxy derivativein the organic layer. Regardless of whether additional solvent is addedto the biphasic mixture, the organic layer containing the desiredC(3)-protected hydroxy derivative is extracted and separated from theaqueous layer containing the by-products and impurities, and the aqueouslayer is discarded. The aqueous/organic extraction may be repeated asdesired, and the organic layers collected and combined.

In order to remove unreacted, excess, or residual protecting groupprecursor and/or undesirable salts of the morphinan alkaloid (e.g.,formed by reaction with the protecting group precursor) from thereaction mixture prior to solvent exchange and quaternization (describedin detail herein), the combined organic layer fractions are preferablywashed with a buffer solution. Typically, the separated organic mixtureincluding the C(3)-protected hydroxy derivative is buffered to a pH ofabout 8.5 to about 9.5 with the buffer solution. In a particularembodiment, the pH of the organic layer is buffered after the protectionreaction(s) to a pH of about 9.0. In general, a variety of pH buffersmay be employed, provided the buffer solution(s) is/are capable ofbuffering the reaction product mixture to a pH within the desired pHrange and/or the buffer solutions do not otherwise affect the morphinanalkaloid backbone and the substituents thereon. Suitable buffersolutions include, for example, those comprising a borate buffer (e.g.,tetraborate), a carbonate buffer, a phosphate buffer, a tertiary aminebuffer (e.g., triethanolamine and tris(hydroxymethyl)aminomethane), andcombinations thereof. In a particular embodiment, the buffer solutioncomprises a phosphate buffer. In another particular embodiment, thebuffer solution is a phosphate buffer. In order to remove a substantialportion of the protecting group precursor, reaction times for the bufferwash can range anywhere from several minutes to several hours dependingon the particular reagents utilized. Typically, the organic phasecontaining the C(3)-protected hydroxy derivative is treated with thebuffer solution for about 30 minutes to about 90 minutes; preferablyabout 60 minutes.

Because the C(3)-O-protecting group may be undesirably removed (i.e.,deprotected) in the presence of water, relatively anhydrous conditionsare generally preferable for both the protection reaction(s) and thesubsequent quaternization. Thus, the organic layer is preferablysubjected to drying step to reduce the water content of the organiclayer. A variety of drying techniques may be employed in this stageincluding, for example, distillation, molecular sieves, anhydrous salts,and Dean-Stark traps, for example, are generally effective, among otherconventional drying methods. Where a water scavenger is employed, forexample, a variety of water scavengers may be utilized, provided thatthe presence of the water scavenger does not adversely affect thequaternization reaction or the morphinan alkaloid backbone and thesubstituents thereon (e.g., by deprotection of the C(3)-hydroxy group).Suitable water scavengers include, but are not limited to, compoundscorresponding to the formula: R_(Y)C(OR_(Z))₃, wherein R_(Y) is hydrogenor hydrocarbyl and R_(Z) is hydrocarbyl. Preferably, R_(Y) is hydrogenor alkyl and R_(Z) is alkyl; in this embodiment, for example, the waterscavenger may correspond to trimethoxymethane, trimethoxyethane,trimethoxypropane, trimethoxybutane, trimethoxypentane,triethyoxyethane, triethoxypropane, combinations thereof, and the like.Alternatively, the water scavenger may be a desiccant such as anhydrousinorganic salts that can form hydrates, e.g., magnesium sulfate (MgSO₄)or sodium sulfate (Na₂SO₄). Desiccants, however, are generally lesspreferred due to their tendency to form a suspension in the reactionmixture.

In one embodiment, the water content of the organic layer is reduced bydistillation to remove any water present in the organic layer (e.g.,through formation of an emulsion with the water immiscible solvent).According to this technique, the water removal can be observed, and oncea substantial portion is withdrawn from the system the resultingdewatered organic layer is preferably further treated with additionalprotecting group precursor (e.g., acetic anhydride) to provide morecomplete conversion of the C(3)-hydroxy morphinan to the C(3)-protectedderivative. As noted above with additional protection reactions, thisfurther protection reaction may require less acetic anhydride (or otherprotecting group precursor) as compared to the first or secondprotection reaction, since there will typically be less unprotectedC(3)-hydroxy morphinan present in the organic layer.

After the C(3)-hydroxy protection steps and optional washing andfiltration steps discussed above, the C(3)-O-protected morphinan may bequaternized. Typically, methyl bromide is the preferred agent formethylating C(3)-OH-protected tertiary morphinan alkaloids and thequaternization is carried out in NMP as previously described. It hasbeen discovered, however, that dimethyl sulfate can also be employed asthe methylating agent for the C(3)-hydroxy protected substrate with highyields of the quaternized product. The alkylation using dimethyl sulfateis preferably carried out in toluene in the presence of sodiumcarbonate, however, other bases (NaHCO₃, K₂HPO₄, i-Pr₂Net, 2,6-lutidine,and 1,8-bis(dimethylamino)naphthalene), also afford the desired product,albeit typically in lower yields.

In one embodiment, the hydroxy protecting group is the acetate groupwhen the alkaloid substrate is naltrexone and a typical sequence ofreactions is shown in Scheme 2 below, wherein R² and X are as defined inconnection with Formulae 1 and 1A.

In this embodiment, the C(3)-OH protection is effected in a basic mediumcomprising i-Pr₂NEt, 2,6-Lutidine, or aqueous solutions of NaOH, NaHCO₃,Na₂CO₃, or K₂HPO₄. Further, in this embodiment, the alkylating agent(i.e., R₂X) comprises a methyl, ethyl, propyl, allyl, cyclopropyl,propargyl or benzyl salt of an anion such as a halide, sulfate,sulfonate, fluorosulfonate, methylsulfate, ethylsulfate,trifluoromethane-sulfonate, hexachloroantimonate, hexafluorophosphate,or tetrafluoroborate. Representative examples include methyl bromide,dimethyl sulfate, diethyl sulfate, methyl fluorosulfonate,trimethyloxonium fluoroborate, triethyloxonium fluoroborate,trimethyloxonium hexachloroantimonate, n-propyl or n-octyltrifluoromethane sulfonate, trimethyloxonium hexafluorophosphate, methyltrifluoromethane sulfonate, and allyl trifluoromethanesulfonate.Typically, the alkylating agent is an alkyl halide or sulfate.Preferably, the alkylating agent is MeBr. Alternatively, oxymorphone maybe substituted for naltrexone and a cyclopropylmethyl alkylating agentmay be substituted for the methylating agent in Reaction Scheme 2 toyield S-methylnaltrexone.

The quaternization of the C(3)-OH-protected alkaloid morphinan substrateis typically carried out at a low pressure (≦2 atm) in the temperaturerange of from about 60 to about 105° C. Preferably, the reaction iscarried out within a temperature range of about 60 to 85° C. Typically,the reaction lasts for a duration of about 6 h-24 h; preferably theduration is for about 16 h-22 h. In a preferred embodiment, N-alkylationof the C(3)-OH-protected alkaloid morphinan substrate is carried outwith MeBr in NMP; at about 60-85° C.; for a duration of between 16 h-22h. Typically, modest pressure differentials of about 4 psi are realizedupon addition of MeBr. Upon completion of the quaternization reaction,the naltrexone methobromide is generated by acid hydrolysis to removethe C(3)-O-protecting group and precipitation from alcohol.

In order to provide the C(3)-O-protected morphinan in the desiredsolvent for the quaternization (e.g., NMP), certain embodiments employsolvent exchange techniques on the reaction product mixture resultingfrom the single or multiple protection reaction(s) (i.e., the organicphase containing the C(3)-protected hydroxy derivative). Generally, inthe solvent exchange, the first solvent preferred in the protectionreactions (e.g., the water immiscible solvent) is removed and replacedwith a second solvent preferred in the quaternization reaction (e.g.,NMP). Thus, the solvent exchange is accomplished by concentrating theprotection reaction mixture, thus forming a concentrate including theC(3)-protected hydroxy derivative, and adding the second solventpreferred for the quaternization reaction to the concentrate. In apreferred embodiment, the concentrate is formed by distilling theorganic phase to remove all, substantially all, or part of the organicsolvent, leaving a concentrate or oil including the C(3)-protectedhydroxy derivative. To affect the solvent exchange by distillation, forexample, the organic phase may be heated to the boiling point of theprotection reaction solvent (i.e., the water immiscible solvent) todistill (either atmospheric or reduced pressure) such solvent from thereaction product. Similarly, if the water immiscible solvent for theprotection reaction forms an azeotrope with water, then part or all ofthe organic solvent with water may be removed by distillation of theazeotrope. Other methods of concentrating the organic layer, however,may be employed and will be apparent to one of skill in the art.

After concentration of the C(3)-protected hydroxy derivative and removalof the water immiscible solvent and other undesirable substances in thereaction mixture (e.g., water, excess or unreacted protecting groupprecursor, by-products, etc.) is accomplished (e.g., by distillation),the C(3)-O-protected morphinan generally remains in the form ofconcentrate. Where all or substantially all of the organic solvent hasbeen removed, the concentrate may be in the form an oil including theC(3)-O-protected morphinan. In the instances where the preferredalkylating agent cannot be effectively added to the concentrate in amanner that will result in quaternization, the concentrate may bedissolved in the preferred solvent for the quaternization reaction(i.e., dissolution of the concentrate or oil in the solvent). Suitablesolvents for the quaternization reaction are described elsewhere herein,and include NMP and dimethyl sulfate. Preferably, the dissolutionsolvent is an anhydrous solvent system as described above. In aparticular embodiment, additional protecting group precursor may beadded to the concentrate in addition to the second (quaternization)solvent in an effort to further provide C(3)-O-protected morphinansubstrate material (i.e., in a second, third, etc., protectionreaction).

In an embodiment, hydrolysis of the C(3)-O-protected quaternized productis effected in aqueous HBr. Approximately 0.5 to about 1.5 equivalentsof HBr is typically employed (based on C(3)-acetoxy naltrexone);preferably the ratio of HBr to C(3)-acetoxy naltrexone is about 1:1. Theacidic mixture is stirred at about 60-65° C. for approximately 30-60minutes for removal of residual MeBr, then heated to about 75-85° C.,and stirred until hydrolysis of C(3)-acetoxy naltrexone methobromide iscomplete as monitored by periodic HPLC analysis of samples. Typically,the hydrolysis is complete within 5 hours.

Upon removal of the C(3)-hydroxy group by way of hydrolysis as describedabove, any residual or unreacted alkylating agent present in thereaction mixture may result in undesirable C(3)-O-alkylation of theC(3)-hydroxy group. For instance, methyl bromide alkylating agent cancause the undesirable formation of a C(3)-O-methyl morphinan quaternaryproduct. Thus, it is generally preferable to quench the quaternizationreaction and purge the alkylating agent from the system. This can beaccomplished, for example, by introducing a purge agent into thereaction mixture/vessel following quaternization and prior tohydrolysis. A variety of quench/purge agents may be employed, and thechoice of a particular purge agent may depend on the particularalkylating agent selected and/or the various other process conditions.For instance, where methyl bromide is used as the alkylating agent, thepurge agent preferably comprises a bromide-containing agent to assist inthe removal (purge) of the methyl bromide from the system.

In a particular embodiment in which methyl bromide is employed in thequaternization reaction, the purge agent introduced to the system afterquaternization is hydrogen bromide or a salt thereof (e.g., atrialkylammonium hydrobromide such as triethylammonium hydrobromide).The bromide-containing purge agent is generally introduced in thepresence of a solvent. The solvent for the purge agent is generally onewhich is compatible with hydrogen bromide (or salts thereof) and whichwill not adversely affect the quaternary morphinan. Suitable solventsinclude various carboxylic acids such as acetic acid; aprotic,non-nucleophilic solvents (e.g., NMP); esters (such as, for example,methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate, and ethyl formate); and combinations thereof.The concentration of bromide in the purge agent is not narrowlycritical; generally only a catalytic amount of bromide is necessary toaffect the desired removal of methyl bromide from the reaction vessel.Thus, the concentration of hydrogen bromide (or salt thereof) in thesolvent can vary from less than 1% (w/w) to nearly 100% (w/w); in apreferred embodiment, the purge agent comprises 33% hydrogen bromide orsalt thereof in acetic acid.

The product of the acid hydrolysis of the quaternizedC(3)-hydroxy-protected alkaloid morphinan is precipitated by addition ofalcohol to the cooled acidic solution under a nitrogen atmosphere. Inthe embodiment described above, the mixture is cooled to about 50-55° C.and an optimal amount of methanol (1.0 wt. equiv based on the initialNMP) is added for precipitation of naltrexone methobromide. Finally, themixture is cooled to room temperature and then stirred for about 1 hourat approximately 0-5° C. for complete precipitation of the product(monitored by HPLC analysis). The product is then filtered, washed withcold methanol (about 1-2 mL/g C(3)-acetoxy naltrexone), and isolated asa wet cake. The product is optimally recrystallized utilizing optimizedconditions (about 1.5-2.0 mL water/g naltrexone methobromide, about3.0-4.0 mL methanol/g naltrexone methobromide, and about 12-24 mole %HBr based on naltrexone methobromide) to afford purified naltrexonemethobromide in high yields and purity.

The protection, quaternization, purge, and hydrolysis steps may becarried out in the order as described, and/or variousextraction/separation and wash steps may be interdispersed between thesevarious stages as described above.

In one embodiment, the process of the invention comprises (a) a firstprotection step, (b) a solvent extraction/separation step, (c) a dryingstep, (d) a second protection step, (e) a concentration step, (f) adissolving step, (g) a quaternization step, and (h) a deprotection step,whereby each of steps (a)-(h) are substantially as described above. Inanother embodiment, the process of the invention comprises (a) a firstprotection step, (b) a solvent extraction/separation step, (c) a secondprotection step, (d) a concentration step, (e) a dissolving step, (f) aquaternization step, and (g) a deprotection step, whereby each of steps(a)-(g) are substantially as described above. In another embodiment, theprocess of the invention comprises (a) a first protection step, (b) a pHadjustment step, (c) a solvent extraction/separation step, (d) a dryingstep, (e) a second protection step, (f) a concentration step, (g) adissolving step, (h) a quaternization step, and (i) a deprotection step,whereby each of steps (a)-(i) are substantially as described above.According to each of these embodiments, for example, the process mayfurther comprise one or more of the following steps: (1) repeating theprotection step and the pH adjustment step (if present); (2) a purgestep prior to the deprotecting step; and (3) a buffer wash step prior tothe drying step. In another embodiment, the process of the inventioncomprises (a) a first protection step, (b) a second protection step, (c)a filtration step, (d) an solvent extraction/separation step, (e) abuffer wash step, (f) a water reduction step; (g) a third protectionstep, (h) a concentration step, (i) a quaternization step, (j) a purgestep, and (k) a hydrolysis step, whereby each of steps (a)-(k) aresubstantially as described above.

The sequence of steps for the preparation of naltrexone methobromide inaccordance with certain of the preferred embodiments of the process ofthe present invention are described above. Advantageously, these stepslead to the conversion of naltrexone base to naltrexone methobromide inhigh yield, with high stereoselectivity for the R-isomer (relative tothe nitrogen atom) over the S-isomer (relative to the nitrogen atom) ofnaltrexone methobromide and relatively low levels of the C(3)-O-methylderivatives of naltrexone methobromide (in either of its R- orS-isomeric forms (i.e., R-MNTX and S-MNTX, respectively)), with R-MNTXand S-MNTX corresponding to the following structures:

and the C(3)-O-methyl derivatives of R-MNTX and S-MNTX corresponding tothe above structures with the phenolic C(3)-hydroxy group being replacedwith a C(3)-O-methyl group. For example, the reaction product mixturewill typically contain at least 70% (w/w) of R-naltrexone methobromide,at least 1% (w/w) of S-naltrexone methobromide, at least 1% (w/w)naltrexone, but no more than 0.2% (w/w) of C(3)-O-methyl derivative ofnaltrexone methobromide (in each of its isomeric forms), based upon thecombined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-methyl derivative of naltrexone methobromide, andnaltrexone in the reaction product mixture (i.e., in the composition).More typically, the reaction product mixture typically includes from 2%to 5% (w/w) naltrexone, more typically 2% to 4% (w/w) naltrexone, basedupon the combined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-methyl derivative of naltrexone methobromide, andnaltrexone in the reaction product mixture (i.e., in the composition).The reaction product mixture also typically includes from 5% to 10%(w/w) of S-naltrexone methobromide, more typically 6% to 7% (w/w), basedupon the combined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-methyl derivative of naltrexone methobromide, andnaltrexone in the reaction product mixture. In a preferred embodiment,the reaction product mixture contains less than 0.15% (w/w)C(3)-O-methyl derivative of naltrexone methobromide (in each of itsisomeric forms), more preferably less than 0.1% (w/w) C(3)-O-methylderivative of naltrexone methobromide (in each of its isomeric forms),and still more preferably about 0.05% to 0.10% (w/w) C(3)-O-methylderivative of naltrexone methobromide (in each of its isomeric forms),based upon the combined weight of the R-naltrexone methobromide,S-naltrexone methobromide, C(3)-O-methyl derivative of naltrexonemethobromide, and naltrexone in the reaction product mixture (i.e., inthe composition). The reaction product mixture preferably comprises atleast 75% (w/w) R-naltrexone methobromide, more preferably at least 80%(w/w) R-naltrexone methobromide, and still more preferably at least 85%R-naltrexone methobromide, based upon the combined weight of theR-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-methylderivative of naltrexone methobromide, and naltrexone in the reactionproduct mixture (i.e., in the composition). Stated differently, incertain embodiments the weight ratio of the R-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the reaction product mixture is at least 150:1. More preferably inthese embodiments, the weight ratio of the R-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the reaction product mixture is at least 250:1(R-isomer:C(3)-O-methyl). Thus, for example, the weight ratio of theR-isomer of naltrexone methobromide to the C(3)-O-methyl derivative ofnaltrexone methobromide in the reaction product mixture may be at least500:1, or at least 750:1, or at least 1,000:1 (R-isomer:C(3)-O-methyl).Similarly, the weight ratio of the S-isomer of naltrexone methobromideto the C(3)-O-methyl derivative of naltrexone methobromide in thereaction product mixture is typically at least 5:1(S-isomer:C(3)-O-methyl). More typically, the weight ratio of S-isomerof naltrexone methobromide to the C(3)-O-methyl derivative of naltrexonemethobromide in the reaction product mixture is at least 10:1(S-isomer:C(3)-O-methyl). Still more typically, the weight ratio ofS-isomer of naltrexone methobromide to the C(3)-O-methyl derivative ofnaltrexone methobromide in the reaction product mixture is at least 50:1(S-isomer:C(3)-O-methyl). Finally, the weight ratio of naltrexone toC(3)-O-methyl derivative of naltrexone methobromide in the reactionproduct mixture is typically at least 5:1 (naltrexone:C(3)-O-methyl).More typically, the weight ratio of naltrexone to the C(3)-O-methylderivative of naltrexone methobromide in the reaction product mixture isat least 10:1 (naltrexone:C(3)-O-methyl). Still more typically, theweight ratio of naltrexone to the C(3)-O-methyl derivative of naltrexonemethobromide in the reaction product mixture is at least 50:1(naltrexone:C(3)-O-methyl). In combination, in one embodiment the weightratio of R-isomer of naltrexone methobromide to the C(3)-O-methylderivative of naltrexone methobromide in the reaction product mixture isat least 150:1 (R-isomer:C(3)-O-methyl), the weight ratio of S-isomer ofnaltrexone methobromide to the C(3)-O-methyl derivative of naltrexonemethobromide in the reaction product mixture is at least 5:1(S-isomer:C(3)-O-methyl), and the weight ratio of naltrexone toC(3)-O-methyl derivative of naltrexone methobromide in the reactionproduct mixture is at least 5:1 (naltrexone:C(3)-O-methyl). Moretypically, the weight ratio of R-isomer of naltrexone methobromide tothe C(3)-O-methyl derivative of naltrexone methobromide in the reactionproduct mixture is at least 250:1 (R-isomer:C(3)-O-methyl), the weightratio of S-isomer of naltrexone methobromide to the C(3)-O-methylderivative of naltrexone methobromide in the reaction product mixture isat least 10:1 (S-isomer:C(3)-O-methyl), and the weight ratio ofnaltrexone to C(3)-O-methyl derivative of naltrexone methobromide in thereaction product mixture is at least 5:1 (naltrexone:C(3)-O-methyl).Still more typically, the weight ratio of R-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the reaction product mixture is at least 500:1(R-isomer:C(3)-O-methyl), the weight ratio of S-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the reaction product mixture is at least 50:1(S-isomer:C(3)-O-methyl), and the weight ratio of naltrexone toC(3)-O-methyl derivative of naltrexone methobromide in the reactionproduct mixture is at least 5:1 (naltrexone:C(3)-O-methyl).

The final reaction product mixture is generally in the form of asolution or a slurry (which may include precipitated material)containing the above-described species. Because the reaction productmixture (e.g., the slurry or the solution) contains such low levels ofC(3)-O-methyl derivative of naltrexone methobromide, purification stepsare simplified. Thus, a crystallization product obtained from thereaction product mixture will contain relatively low levels of theC(3)-O-methyl derivative of naltrexone methobromide relative toR-naltrexone methobromide, S-naltrexone methobromide, and naltrexone.For example, the crystallization product will contain no more than 0.25%(w/w) of C(3)-O-methyl derivative of naltrexone methobromide (in each ofits isomeric forms), based upon the combined weight of the R-naltrexonemethobromide, S-naltrexone methobromide, C(3)-O-methyl derivative ofnaltrexone methobromide, and naltrexone in the crystallization product(i.e., in the composition). More typically, the crystallization producttypically includes from 0.25% to 1% (w/w) naltrexone, more typically0.5% to 0.75% (w/w) naltrexone, based upon the combined weight of theR-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-methylderivative of naltrexone methobromide, and naltrexone in thecrystallization product (i.e., in the composition). The crystallizationproduct also typically includes from 1% to 2% (w/w) of S-isomer ofnaltrexone methobromide, more typically 1% to 1.5% (w/w), based upon thecombined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-methyl derivative of naltrexone methobromide, andnaltrexone in the crystallization product. In a preferred embodiment,the crystallization product contains less than 0.15% (w/w) C(3)-O-methylderivative of naltrexone methobromide (in each of its isomeric forms),more preferably less than 0.1% (w/w) C(3)-O-methyl derivative ofnaltrexone methobromide (in each of its isomeric forms), and still morepreferably about 0.05% to 0.10% (w/w) C(3)-O-methyl derivative ofnaltrexone methobromide (in each of its isomeric forms), based upon thecombined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-methyl derivative of naltrexone methobromide, andnaltrexone in the crystallization product (i.e., in the composition).Stated differently, in certain embodiments the weight ratio of theR-isomer of naltrexone methobromide to the C(3)-O-methyl derivative ofnaltrexone methobromide in the crystallization product is at least 150:1(R-isomer:C(3)-O-methyl). More preferably in these embodiments, theweight ratio of the R-isomer of naltrexone methobromide to theC(3)-O-methyl derivative of naltrexone methobromide in thecrystallization product is at least 250:1 (R-isomer:C(3)-O-methyl).Thus, for example, the weight ratio of the R-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the crystallization product may be at least 500:1, or at least 750:1,or at least 1,000:1 (R-isomer:C(3)-O-methyl). Similarly, the weightratio of the S-isomer of naltrexone methobromide to the C(3)-O-methylderivative of naltrexone methobromide in the crystallization product istypically at least 2:1 (S-isomer:C(3)-O-methyl). More typically, theweight ratio of S-isomer of naltrexone methobromide to the C(3)-O-methylderivative of naltrexone methobromide in the crystallization product isat least 5:1 (S-isomer:C(3)-O-methyl). Still more typically, the weightratio of S-isomer of naltrexone methobromide to the C(3)-O-methylderivative of naltrexone methobromide in the crystallization product isat least 10:1 (S-isomer:C(3)-O-methyl). Still more typically, the weightratio of S-isomer of naltrexone methobromide to the C(3)-O-methylderivative of naltrexone methobromide in the crystallization product isat least 15:1 (S-isomer:C(3)-O-methyl). Finally, the weight ratio ofnaltrexone to C(3)-O-methyl derivative of naltrexone methobromide in thecrystallization product is typically at least 2:1(naltrexone:C(3)-O-methyl). More typically, the weight ratio ofnaltrexone to the C(3)-O-methyl derivative of naltrexone methobromide inthe crystallization product is at least 5:1 (naltrexone:C(3)-O-methyl).Still more typically, the weight ratio of naltrexone to theC(3)-O-methyl derivative of naltrexone methobromide in thecrystallization product is at least 10:1 (naltrexone:C(3)-O-methyl). Incombination, in one embodiment the weight ratio of R-isomer ofnaltrexone methobromide to the C(3)-O-methyl derivative of naltrexonemethobromide in the crystallization product is at least 150:1(R-isomer:C(3)-O-methyl), the weight ratio of S-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the crystallization product is at least 2:1 (S-isomer:C(3)-O-methyl),and the weight ratio of naltrexone to C(3)-O-methyl derivative ofnaltrexone methobromide in the crystallization product is at least 2:1(naltrexone:C(3)-O-methyl). More typically, the weight ratio of R-isomerof naltrexone methobromide to the C(3)-O-methyl derivative of naltrexonemethobromide in the crystallization product is at least 250:1(R-isomer:C(3)-O-methyl), the weight ratio of S-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the crystallization product is at least 5:1 (S-isomer:C(3)-O-methyl),and the weight ratio of naltrexone to C(3)-O-methyl derivative ofnaltrexone methobromide in the crystallization product is at least 2:1(naltrexone:C(3)-O-methyl). Still more typically, the weight ratio ofR-isomer of naltrexone methobromide to the C(3)-O-methyl derivative ofnaltrexone methobromide in the crystallization product is at least 500:1(R-isomer:C(3)-O-methyl), the weight ratio of S-isomer of naltrexonemethobromide to the C(3)-O-methyl derivative of naltrexone methobromidein the crystallization product is at least 10:1(S-isomer:C(3)-O-methyl), and the weight ratio of naltrexone toC(3)-O-methyl derivative of naltrexone methobromide in thecrystallization product is at least 2:1 (naltrexone:C(3)-O-methyl).

Similarly, the process of the present invention may be used when thedesired product is S-naltrexone methobromide. In this embodiment,however, oxymorphone is used instead of naltrexone as the substrate andthe nitrogen atom of the substrate is alkylated with a cyclopropylmethylalkylating agent such as cyclopropylmethylbromide. To minimize theformation of the corresponding C(3)-O-cyclopropylmethyl-5-naltrexonemethobromide, the C(3)-hydroxy group of oxymorphone may be protectedwith a hydroxy protecting group during the cyclopropylmethylationreaction as otherwise described herein for the N-methylation ofnaltrexone and N-alkylation of other morphinan alkaloid substratescorresponding to Formula 1, 2, 3, 4, 11, 22, 222, etc. For example, theC(3)-hydroxy group of oxymorphone may be protected with an acetyl groupas otherwise described in connection with the protection of theC(3)-hydroxy group of naltrexone in the synthesis of R-naltrexonemethobromide and the C(3)-hydroxy protected oxymorphone substrate isN-alkylated using a cyclopropylmethyl alkylating agent as otherwisedescribed in connection with the N-methylation of naltrexone in thesynthesis of R-naltrexone methobromide. Advantageously, these steps leadto the conversion of oxymorphone base to naltrexone methobromide in highyield, with high stereoselectivity for the S-isomer (relative to thenitrogen atom) over the R-isomer (relative to the nitrogen atom) ofnaltrexone methobromide and relatively low levels of theC(3)-O-cyclopropylmethyl derivatives of naltrexone methobromide ineither of its R- or S-isomeric forms (i.e., R-MNTX and S-MNTX,respectively). For example, the reaction product mixture will typicallycontain at least 70% (w/w) of S-naltrexone methobromide, at least 1%(w/w) of R-naltrexone methobromide, at least 1% (w/w) oxymorphone, butno more than 0.25% (w/w) of C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide (in each of its isomeric forms), based upon thecombined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide, and oxymorphone in the reaction product mixture (i.e., inthe composition). More typically, the reaction product mixture typicallyincludes from 2% to 5% (w/w) oxymorphone, more typically 2% to 4% (w/w)oxymorphone, based upon the combined weight of the R-naltrexonemethobromide, S-naltrexone methobromide, C(3)-O-cyclopropylmethylderivative of naltrexone methobromide, and oxymorphone in the reactionproduct mixture (i.e., in the composition). The reaction product mixturealso typically includes from 5% to 10% (w/w) of R-naltrexonemethobromide, more typically 6% to 7% (w/w), based upon the combinedweight of the R-naltrexone methobromide, S-naltrexone methobromide,C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, andoxymorphone in the reaction product mixture. In a preferred embodiment,the reaction product mixture contains less than 0.15% (w/w)C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (in eachof its isomeric forms), more preferably less than 0.1% (w/w)C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (in eachof its isomeric forms), and still more preferably about 0.05% to 0.10%(w/w) C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (ineach of its isomeric forms), based upon the combined weight of theR-naltrexone methobromide, S-naltrexone methobromide,C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, andoxymorphone in the reaction product mixture (i.e., in the composition).The reaction product mixture preferably comprises at least 75% (w/w)S-naltrexone methobromide, more preferably at least 80% (w/w)S-naltrexone methobromide, and still more preferably at least 85%S-naltrexone methobromide, based upon the combined weight of theR-naltrexone methobromide, S-naltrexone methobromide,C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, andoxymorphone in the reaction product mixture (i.e., in the composition).Stated differently, in certain embodiments the weight ratio of theS-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the reaction product mixture isat least 150:1. More preferably in these embodiments, the weight ratioof the S-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture is at least 250:1(S-isomer:C(3)-O-cyclopropylmethyl). Thus, for example, the weight ratioof the S-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture may be at least 500:1, or at least 750:1, or atleast 1,000:1 (S-isomer:C(3)-O-cyclopropylmethyl). Similarly, the weightratio of the R-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture is typically at least 5:1(R-isomer:C(3)-O-cyclopropylmethyl). More typically, the weight ratio ofR-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the reaction product mixture isat least 10:1 (R-isomer:C(3)-O-cyclopropylmethyl). Still more typically,the weight ratio of R-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture is at least 50:1(R-isomer:C(3)-O-cyclopropylmethyl). Finally, the weight ratio ofoxymorphone to C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide in the reaction product mixture is typically at least 5:1(oxymorphone:C(3)-O-cyclopropylmethyl). More typically, the weight ratioof oxymorphone to the C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide in the reaction product mixture is at least 10:1(oxymorphone:C(3)-O-cyclopropylmethyl). Still more typically, the weightratio of oxymorphone to the C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide in the reaction product mixture is at least 50:1(oxymorphone:C(3)-O-cyclopropylmethyl). In combination, in oneembodiment the weight ratio of S-isomer of naltrexone methobromide tothe C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide inthe reaction product mixture is at least 150:1(S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of R-isomer ofnaltrexone methobromide to the C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide in the reaction product mixture is at least 5:1(R-isomer:C(3)-O-cyclopropylmethyl), and the weight ratio of oxymorphoneto C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture is at least 5:1(oxymorphone:C(3)-O-cyclopropylmethyl). More typically, the weight ratioof S-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the reaction product mixture isat least 250:1 (S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio ofR-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the reaction product mixture isat least 10:1 (R-isomer:C(3)-O-cyclopropylmethyl), and the weight ratioof oxymorphone to C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide in the reaction product mixture is at least 5:1(oxymorphone:C(3)-O-cyclopropylmethyl). Still more typically, the weightratio of S-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture is at least 500:1(S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of R-isomer ofnaltrexone methobromide to the C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide in the reaction product mixture is at least 50:1(R-isomer:C(3)-O-cyclopropylmethyl), and the weight ratio of oxymorphoneto C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thereaction product mixture is at least 5:1(oxymorphone:C(3)-O-cyclopropylmethyl).

The final reaction product mixture is generally in the form of asolution or a slurry (which may include precipitated material)containing the above-described species. Because the reaction productmixture (e.g., the slurry or the solution) contains such low levels ofC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide,purification steps are simplified. Thus, a crystallization productobtained from the reaction product mixture will contain relatively lowlevels of the C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide relative to R-naltrexone methobromide, S-naltrexonemethobromide, and oxymorphone. For example, the crystallization productwill typically contain no more than 0.25% (w/w) ofC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (in eachof its isomeric forms), based upon the combined weight of theR-naltrexone methobromide, S-naltrexone methobromide,C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, andoxymorphone in the crystallization product (i.e., in the composition).More typically, the crystallization product typically includes from0.25% to 1% (w/w) oxymorphone, more typically 0.5% to 0.75% (w/w)oxymorphone, based upon the combined weight of the R-naltrexonemethobromide, S-naltrexone methobromide, C(3)-O-cyclopropylmethylderivative of naltrexone methobromide, and oxymorphone in thecrystallization product (i.e., in the composition). The crystallizationproduct also typically includes from 1% to 2% (w/w) of R-isomer ofnaltrexone methobromide, more typically 1% to 1.5% (w/w), based upon thecombined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide, and oxymorphone in the crystallization product. In apreferred embodiment, the crystallization product contains less than0.15% (w/w) C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide (in each of its isomeric forms), more preferably less than0.1% (w/w) C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide (in each of its isomeric forms), and still more preferablyabout 0.05% to 0.10% (w/w) C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide (in each of its isomeric forms), based upon thecombined weight of the R-naltrexone methobromide, S-naltrexonemethobromide, C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide, and oxymorphone in the crystallization product (i.e., inthe composition). Stated differently, in certain embodiments the weightratio of the S-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is at least 150:1(S-isomer:C(3)-O-cyclopropylmethyl). More preferably in theseembodiments, the weight ratio of the S-isomer of naltrexone methobromideto the C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide inthe crystallization product is at least 250:1(S-isomer:C(3)-O-cyclopropylmethyl). Thus, for example, the weight ratioof the S-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product may be at least 500:1, or at least 750:1, or atleast 1,000:1 (R-isomer:C(3)-O-cyclopropylmethyl). Similarly, the weightratio of the R-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is typically at least 2:1(R-isomer:C(3)-O-cyclopropylmethyl). More typically, the weight ratio ofR-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the crystallization product isat least 5:1 (R-isomer:C(3)-O-cyclopropylmethyl). Still more typically,the weight ratio of R-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is at least 10:1(R-isomer:C(3)-O-cyclopropylmethyl). Still more typically, the weightratio of R-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is at least 15:1(R-isomer:C(3)-O-cyclopropylmethyl). Finally, the weight ratio ofoxymorphone to C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide in the crystallization product is typically at least 2:1(oxymorphone:C(3)-O-cyclopropylmethyl). More typically, the weight ratioof oxymorphone to the C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide in the crystallization product is at least 5:1(oxymorphone:C(3)-O-cyclopropylmethyl). Still more typically, the weightratio of oxymorphone to the C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide in the crystallization product is at least 10:1(oxymorphone:C(3)-O-cyclopropylmethyl). In combination, in oneembodiment the weight ratio of S-isomer of naltrexone methobromide tothe C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide inthe crystallization product is at least 150:1(S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of R-isomer ofnaltrexone methobromide to the C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide in the crystallization product is at least 2:1(R-isomer:C(3)-O-cyclopropylmethyl), and the weight ratio of oxymorphoneto C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is at least 2:1(oxymorphone:C(3)-O-cyclopropylmethyl). More typically, the weight ratioof S-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the crystallization product isat least 250:1 (S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio ofR-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethylderivative of naltrexone methobromide in the crystallization product isat least 5:1 (R-isomer:C(3)-O-cyclopropylmethyl), and the weight ratioof oxymorphone to C(3)-O-cyclopropylmethyl derivative of naltrexonemethobromide in the crystallization product is at least 2:1(oxymorphone:C(3)-O-cyclopropylmethyl). Still more typically, the weightratio of S-isomer of naltrexone methobromide to theC(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is at least 500:1(S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of R-isomer ofnaltrexone methobromide to the C(3)-O-cyclopropylmethyl derivative ofnaltrexone methobromide in the crystallization product is at least 10:1(R-isomer:C(3)-O-cyclopropylmethyl), and the weight ratio of oxymorphoneto C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in thecrystallization product is at least 2:1(oxymorphone:C(3)-O-cyclopropylmethyl).

Viewed more generally, purification of the reaction product mixture to acrude product from the synthesis described above yields N-alkyl productof about 98% purity; assessed by HPLC relative to an analyticalstandard. The treatment of the protection and quaternization reactionmixtures according to the various processes and embodiments describedherein results in a significantly reduced concentration of C(3)-O-alkylmorphinan alkaloid impurity in the compositions of the invention.Compositions that may include the quaternized product(s) described aboveinclude both final product mixtures (i.e., the crude final productmixture, e.g., dissolved in a solution) and/or the final crystallizedproducts (i.e., a solid comprising the quaternized product in acrystalline form). In a particular embodiment, the composition includesthe final crude product mixture. In another particular embodiment, thecomposition includes the final product mixture after a firstcrystallization.

Another aspect of the present invention, therefore, is a compositioncomprising a C(3)-hydroxy quaternary N-substituted morphinan alkaloidcorresponding to Formula 11A and no more than 0.1% (w/w) of aC(3)-alkoxy alkaloid corresponding to Formula 11C, relative to theamount of the C(3)-hydroxy quaternary N-substituted morphinan alkaloidcorresponding to Formula 11A in the composition, wherein the alkaloidscorresponding to Formula 11A and Formula 11C have the structures:

wherein

A is —C(O)—, —C(S)—, —C(═CH₂)—, —CH(A₁)- or —C(A₁)=,

A₁ is hydroxy, alkoxy, or acyloxy,

R¹ is hydrocarbyl or substituted hydrocarbyl;

R² is alkyl,

X¹ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate,methylsulfate, ethylsulfate, trifluoromethanesulfonate,hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;

Y, if present, is hydrogen, hydroxy, protected hydroxy, alkoxy, oracyloxy, and

the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8,and 8 and 14, respectively, represent (i) carbon-carbon single bonds;(ii) carbon-carbon single bonds between positions 6 and 7 and betweenpositions 8 and 14, and a double bond between positions 7 and 8; or(iii) conjugated carbon-carbon double bonds between positions 6 and 7and positions 8 and 14, with the proviso that Y is not present if thereis a double bond between the carbons at positions 8 and 14.

As noted above, the compositions of the invention may include the crudefinal product mixtures (i.e., prior to any crystallization steps), thefinal product mixture after an initial crystallization, or the finalcrystallized active pharmaceutical ingredient (e.g., that this in finalform). The processes of the present invention are particularlyadvantageous in that the presence of undesirable impurities and otherspecies is significantly reduced at the crude final product mixturestage, prior to any crystallization. Subsequent crystallization stepsmay serve to further reduce the levels of such species below theiralready desirably low levels. In one embodiment, the C(3)-hydroxyquaternary N-substituted morphinan alkaloid present in the compositionis naltrexone methobromide.

As noted above, the composition includes no more than about 0.1% of aC(3)-O-alkyl quaternary or tertiary N-substituted morphinan alkaloidimpurity, relative to the total alkaloid content. For example, thecomposition may include less than about 0.05% of a C(3)-O-alkylquaternary or tertiary N-substituted morphinan alkaloid impurity,relative to the total alkaloid content. Preferably, the compositionincludes no more than about 0.01% of a C(3)-O-alkyl quaternary ortertiary N-substituted morphinan alkaloid impurity, relative to thetotal alkaloid content. For example, the composition may include lessthan about 0.005% of a C(3)-O-alkyl quaternary or tertiary N-substitutedmorphinan alkaloid impurity, relative to the total alkaloid content.More preferably, the composition includes no more than about 0.001% of aC(3)-O-alkyl quaternary or tertiary N-substituted morphinan alkaloidimpurity, relative to the total alkaloid content. For example, thecomposition may include less than about 0.0005% of a C(3)-O-alkylquaternary or tertiary N-substituted morphinan alkaloid impurity,relative to the total alkaloid content. Still more preferably, nodetectable amount of a C(3)-O-alkyl quaternary or tertiary N-substitutedmorphinan alkaloid impurity is present in the composition.

DEFINITIONS

As used herein, “Ac” means acetyl, “Bn” means benzyl, “Bs” means brosyl,“Bz” means benzoyl, “Ms” means mesyl, “THP” means tetrahydropyranyl, and“Ts” means tosyl.

The term “anhydrous solvent” as used herein refers to solventscontaining less than 0.5% by weight water, preferably maintained andhandled under nitrogen gas during a reaction.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl,acyloxy, nitro, tertiary amino, amido, nitro, cyano, ketals, acetals,esters and ethers.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain. They may be straight or branched chain or cyclic andinclude methyl, ethyl, propyl, isopropyl, allyl, benzyl, hexyl and thelike.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R isR¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo, and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The term “halide” refers to fluoride, chloride, bromide, or iodide ions.

The term “narcotics” as used herein refers to drugs that depress thecentral nervous system and relieve pain when used in moderate doses.

The term “opioid” as used herein refers to non-opium-derived (syntheticor naturally occurring) narcotics that act on the central nervous systemto decrease the sensation of pain.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

The following non-limiting examples are provided to further illustratethe present invention.

Reagents

A dehydrated naltrexone base was used in experiments that did notrequire phenolic C(3)-hydroxide protection. This base was prepared fromnaltrexone hydrochloride which was dried under vacuum until the watercontent was about 2% by Karl-Fischer analysis. A hydrated naltrexonebase (the dihydrate) was used in the experiments that require protectionof the phenolic hydroxide.

A bottle of hydrogen bromide (HBr) was cooled to −70° C. and1-methyl-2-pyrrolidinone (N-methylpyrrolidone; NMP) was cooled down to−20° C. HBr (13.01 g; 160 mmol) was added into the NMP (130 mL) and thesolution was allowed to warm to room temperature. The solution was thendiluted with NMP to 160.0 mL to form a 1N solution of HBr in NMP(HBr/NMP).

A bottle containing methyl bromide (MeBr; b.p. 4° C.) was cooled down to−10° C. MeBr (50.00 mL) was poured out and weighed (88.53 g; d=1.77g/mL). The methyl bromide was added into a pre-cooled bottle containing1-Methyl-2-Pyrrolidinone (NMP) {50.00 mL; 54.39 g, −10° C.} to formapproximately 100 mL solution at −10° C. (MeBr/NMP).

Comparative Example A Synthesis of Naltrexone Methobromide

A comparative N-methylation was performed, by addition of 1.5 equiv.MeBr/NMP to a bulk suspension of 12.5 Kg anhydrous naltrexone in NMP(1.5 volume equivalents (vol. equiv.)) following the scaled-up versionof the general procedure disclosed in Example 1 of WO 2004/043964. Theyield of crude naltrexone methobromide product was 9.43 Kg. The productyield was 60.9 mmol. % in Comparative Example A, and 12.6 mol. % of sideproducts were produced.

Example 1 Synthesis of Naltrexone Methobromide Slow Addition of MeBr

1-methyl-2-pyrrolidinone (N-methylpyrrolidinone, NMP, 150 mL) was addedinto a three-necked, 1000-mL flask and heated to 58° C. under a nitrogenflow. Naltrexone base (100.00 g, a solid, containing 2% water; 287 mmol)was added. The funnel was washed with 25 mL of NMP. The mixture remaineda suspension after 1 hour of heating.

A 50-mL solution of MeBr/NMP (466 mmol MeBr) was transferred into apre-cooled dropping funnel (−10° C.) equipped with a cooling system tomaintain the MeBr at a temperature between −10° C. and 0° C. Nitrogenwas passed over the top of the condenser. The MeBr/NMP solution wasadded drop-wise from the funnel into the naltrexone/NMP suspension over30 minutes and the temperature increased over this time period up to 58°C., The resulting mixture was heated at about 55-58° C. for 20 minutesto form a solution and the heating was continued at about 65° C. withstirring under nitrogen for 12 hours. Solids started to form after 2hours at 65° C. The reaction mixture was cooled to room temperature toyield a thick suspension, 250 mL of acetone was added, and the mixturewas stirred for 1 hour and filtered. The solid was washed with two 25-mLaliquots of acetone and dried under vacuum at 55° C. to give 92.26 g ofa crude product as a white solid. The combined filtrate and washes werecollected (452 g of liquid) for recovery of unreacted naltrexone.

Example 2 Synthesis of Naltrexone Methobromide Slow Addition of MeBr

1-methyl-2-pyrrolidinone (NMP, 50 mL) was added to a three-necked,250-mL flask which was heated to 54° C. and blanketed under nitrogen. 40g of naltrexone base, containing 2% water was added and the funnel waswashed with 10 mL of NMP. The mixture remained as a suspension after 0.5hour of heating.

A 20-mL solution of MeBr/NMP (93.2 mmol MeBr) was transferred into apre-cooled dropping funnel (−10° C.) equipped with a cooling system tomaintain MeBr at between −10 and 0° C. Nitrogen was introduced at thetop of the water condenser (about 20° C.). A 10-mL portion of theMeBr/NMP solution was added drop-wise into the suspension over 15minutes at about 56-58° C. The resulting mixture was heated at about56-58° C. under nitrogen for another 30 minutes. Most of the solidsubstrate was dissolved at this point. The remaining MeBr/NMP solutionwas added drop-wise into the reaction mixture over a 10-minute period atabout 56-58° C. and stirring was maintained at about 57° C. for another10 minutes followed by further heating to about 63-65° C. for 12 hours.After this period, the suspension was cooled to room temperature andstifled for 4 hours. Ninety (90) mL of acetone was added to the reactionmixture and heat was released. The mixture was stirred for 1 hourallowed to cool to room temperature and then filtered. The solid waswashed with four 10-mL aliquots of acetone and dried under vacuum at 55°C. for 19 hours to give 40.22 g of crude product as a white solid. Thecombined washes (mother liquor, 177.5 mL) were collected for recovery ofunreacted naltrexone.

Example 3 Synthesis of Naltrexone Methobromide Slow Addition of MeBr;and Substitution of Chloroform for Acetone

1-methyl-2-pyrrolidinone (NMP, 25 mL) was added into a three-necked250-mL flask and heated to 57° C. under nitrogen. 20 g of naltrexonebase (containing 2% water) was added via a funnel and the funnel waswashed with 5 mL of NMP. The mixture remained as a suspension afterheating for 30 minutes.

A 10-mL solution of MeBr/NMP (93.2 mmol MeBr) was transferred into apre-cooled dropping funnel (−10° C.) equipped with a cooling system tomaintain the MeBr solution at below 0° C. A nitrogen sweep wasintroduced at the top of the attached water-cooled condenser (about 20°C.) and about 7 mL of the MeBr/NMP solution was added drop-wise to thesuspension over 15 minutes at about 56-58° C. The resulting mixture washeated at about 56-58° C. under nitrogen for 30 minutes by which timemost of the solid was dissolved. The remaining MeBr/NMP solution wasadded drop-wise to the reaction mixture over 10 minutes at about 56-58°C. and stirring was continued for an additional 10 minutes followed byheating at about 63-65° C. under nitrogen for 12 hours. A precipitateformed after 2-3 hours. At the end of the 12-hour period, the suspensionwas cooled to room temperature and stirring was continued for anadditional 4 hours.

To the reaction mixture was added 45 mL of CHCl₃. The addition wasexothermic and the temperature of mixture rose to 35° C. from roomtemperature. The mixture was then allowed to cool to room temperaturewith stirring for 1 hour after which the solid suspension was separatedby filtration, washed with three 10-mL portions of CHCl₃ and vacuumdried at 55° C. for 19 hours to yield 19.55 g of crude product as awhite solid. The combined filtrate and washes were collected (motherliquor, 84.5 mL) for recovery of unreacted naltrexone base.

Example 4 Synthesis of Naltrexone Methobromide in Presence of HBr SlowAddition of MeBr and Substitution of Chloroform for Acetone

1-methyl-2-pyrrolidinone (NMP, 33.3 mL) and 15 g of naltrexone base(containing 2% water) were added into a three-necked 250-mL flask undernitrogen. An 11.7 mL solution of 1.00N HBr/NMP and 14 mL of t-BuOH wereadded. The solution was heated to about 54° C., an extra 25.00 g ofnaltrexone base (containing 2% water) was added via a funnel, and thefunnel was washed with 10 mL of NMP. The final mixture remained as asuspension after heating for 30 minutes.

A 20-mL aliquot of MeBr/NMP (186.4 mmol MeBr) was transferred into apre-cooled dropping funnel (−10° C.) equipped with a cooling system tomaintain the MeBr at below 0° C. Nitrogen was introduced at the top ofthe attached water-cooled condenser (about 20° C.). 13 mL of theMeBr/NMP solution was added drop-wise to the suspension over 15 minutesat about 55-57° C. The resulting mixture was heated at approximately55-57° C. under nitrogen for another 30 minutes to form a clearsolution. The remaining MeBr/NMP solution was added drop-wise to thereaction mixture over 10 minutes at approximately 55-57° C., stirred foran additional 10 minutes, then heated to approximately 61-63° C. for 19hours. The resultant suspension was cooled to room temperature, stirredfor 4 hours, and 90 mL of chloroform was added which resulted in heatrelease. After cooling to room temperature and stirring forapproximately 1 hour, the solids were separated by filtration, washedwith four 10-mL portions of chloroform, and dried under vacuum at about55° C. for 19 hours. This afforded 38.58 g of crude product as a whitesolid. The combined washes were collected (mother liquor, 166.5 mL) forrecovery of unreacted naltrexone.

Discussion of the Results of Examples 1-4 and the Comparative Example.

In each of the above examples, the components of the final reactionmixture were analyzed by HPLC and the results tabulated; see Tables 1and 3, and Scheme 3. The identified components are grouped as follows:

-   -   (1) Nal-MeBr=naltrexone methobromide, desired product;    -   (2) Nal=naltrexone=recyclable starting material; and    -   (3) Other side products=Nal-MeBr-isomer, MeO-Nal, MeO-Nal-MeBr;        not recyclable.

The data entered for Examples 1-3 in Table 3 indicate that slow additionof MeBr/NMP over 10-30 minutes increases the yield of naltrexonemethobromide to about 68 to 79%.

The entry for Example 4 in Table 3 represents the effect of the additionof acid (0.1 equiv. HBr). Incorporation of this reagent increased theyield of the product (naltrexone methobromide) to about 77.5% anddecreased the side products to about 5.1%. Addition of HBr suppressesthe ionization of the C(3) hydroxide (phenolic hydroxide) of naltrexoneto form Nal (see Scheme 4) and thereby reduces the chemical reactivityof the C(3) hydroxide toward MeBr. Further, addition of a stronganhydrous acid (HBr) to the reaction system permits use of partiallyhydrated naltrexone (Naltrexone.2H₂O) as a starting material instead ofanhydrous naltrexone thereby eliminating the processing costs associatedwith dehydration of naltrexone. Since an additional reaction step isrequired to prepare anhydrous naltrexone from the hydrate(Naltrexone.2H₂O), addition of HBr would reduce processing costs.

Approximately 13 mol. % of C(3)-O-methyl side products were realized inComparative Example A. In Examples 1-3, the C(3)-O-methyl side productsare reduced about 3-fold to 5-fold. In Example 4 which incorporated theprocess improvements of Examples 1-3, increases in the yield and purityof the quaternized product, naltrexone methobromide was observed (seesummary in Table 2).

The procedures of Examples 1-3 differ from that of Comparative Example Aby

(i) slowing the addition of MeBr/NMP;

(ii) reducing the temperature of the MeBr/NMP (maintained at about 0° C.to −10° C. during addition) into the NMP solution of naltrexone(containing 2% water) at approximately 55-58° C.; and

(iii) extending the reaction period from 10 to 12 hours.

The processes of Examples 1-3 yielded a higher molar percentage of theproduct, naltrexone methobromide (Nal-MeBr) compared to the process ofComparative Example A. In Example 4, 0.1 equiv. of HBr was also addedinto the reaction mixture. The increased hydrogen ion (H⁺) concentrationwas found to depress the formation of side products, e.g., O-methylnaltrexone and O-methyl naltrexone methobromide, thus improving thepurity of the crude product.

TABLE 1 Yield of crude product Example No. Nal. charged KF*% LOD**%Crude Yield Comp. A 12.5 Kg 0.61 0~0.2 9.43 Kg 1 100.00 g 1.22 0.0492.26 g 2 20.00 g 3.06 0.07 18.90 g 3 40.00 g 1.13 0.06 35.92 g 4 40.00g 1.18 0.12 37.56 g *KF is Karl-Fischer test for water. **LOD is theweight loss on drying.

TABLE 2 Crude product quality* Example No. Crude Yield % Nal•MeBr % Nal% O-Methyl Nal Comp A 9.43 Kg 90.26 2.63 6.0 1 92.26 g 84.98 1.81 4.62(area %) 2 18.90 g 96.7 2.10 4.70 (area %) 3 35.92 g 89.32 1.48 5.11(area %) 4 37.56 g 97.36 2.65 1.57 (area %) *The data in Table 2 arewt./wt. % except O-Methyl Nal area % from HPLC analysis.

TABLE 3 Distribution of product and by-products Example No. Mol. %Nal•MeBr* Mol. % Nal** Mol. % Others*** Comp A 60.9 26.5 12.6 1 68.314.8 16.9 2 79.0 10.3 10.7 3 75.1 9.7 15.2 4 77.5 17.4 5.1 *Nal•MeBr:naltrexone methobromide; **Nal: naltrexone; ***O-methyl-Nal:C(3)-O-methyl-naltrexone.

Example 5 Synthesis of C(3)-Acetoxy Naltrexone

Deionized water (600 mL) and naltrexone base (90. g, 0.26 moles (mol))were mixed in a 2-L, three-necked round bottomed flask equipped with amechanical stirrer, addition funnel, and thermocouple. Toluene (300 mL)was added, the mixture was stirred under a nitrogen atmosphere for 5minutes, and NaOH (0.26 mol) was then added as a 10% w/w aqueoussolution via an addition funnel over a 10 minute period. A temperatureincrease from 21.5° C. to 22.6° C. was observed. The resulting solutionwas then stirred for 15 minutes (all solid dissolved) and aceticanhydride (29.61 g, 0.29 mol) was added over a 15-minute period and thetemperature was increased to 27.1° C. The resulting mixture was thenstirred for 15 minutes and the pH was adjusted from 6.55 to 10.15 with10 wt. % solution of NaOH (24.2 g, 0.06 mol.). The mixture was stirredfor 10 minutes, the layers were separated and the aqueous layer wasextracted once with toluene (100 mL). The combined organic layers werethen filtered through a Whatman Glass Microfibre Filter (GF/A, 90 mm)and the resulting filtrate was allowed to sit undisturbed for furtherseparation of water. The residual water was removed, and C(3)-acetoxynaltrexone/toluene solution was obtained (459.8 g). The solution wasconcentrated under reduced pressure to afford an amber/yellow oil andthen dissolved in NMP to prepare a 30.0 wt. % solution of the product.

Example 6 Synthesis of Naltrexone Methobromide

To a 1-L, 5-neck, jacketed pressure reactor equipped with a polishedglass stirring shaft, mechanical stirrer, reflux condenser, pressuremanifold, thermowell, and ⅛″ ID MeBr addition line was added a solutionof C(3)-acetoxy naltrexone in NMP (732.2 g of 30% wt/wt solution, 0.57moles). Methyl bromide (107.9 g, 1.14 moles) was then added via asubsurface addition with vigorous stirring over a 1 hour period. Theamount of MeBr added to the reactor was ascertained by a difference inthe initial and final weights of a MeBr lecture bottle. During theaddition, the temperature of the reaction mass increased from 20.8° C.to 32.9° C. (yellow solution) and a maximum pressure of 3-4 psi wasobserved. After the appropriate amount of MeBr was added, the reactorheadspace was evacuated and repressurized with MeBr (to about 2 psi)twice before heating to 60° C. At 60° C., a pressure of 2-4 psi wasobserved. The reaction mixture was stirred overnight (15 hours) and nopressure was observed (a yellow solution resulted). Aqueous HBr (1.0equiv, 0.57 moles, 96.58 g of 48 wt. %) was added slowly at 60° C. overa 30-minute period. The reactor was vented into NMP in order to trapgaseous methyl bromide that was generated during the HBr addition.During the addition, the reaction temperature increased to 63.7° C. Thereaction temperature was then increased to 80° C. over a 1.5 hour periodand the methyl bromide evolution ceased. The mixture was stirred at 80°C. for 2 hours and precipitation was observed. After 5 hours at 80° C.,the slurry was analyzed by HPLC and a minor amount of C(3)-acetoxynaltrexone methobromide was observed (<0.5% by area) was observed. Themixture was then transferred to a 2-L three-neck round bottomed flaskequipped with a glass stirring shaft, mechanical stirrer, refluxcondenser, and thermocouple under a nitrogen atmosphere. The mixture wascooled to 56.2° C. and methanol (512.5 g, 1.0 wt equiv. based on theamount of NMP charged) was added quickly. The temperature decreasedquickly to 41.2° C. and then increased to 42.5° C. upon crystallizationof naltrexone methobromide. The slurry was then cooled to 29.7° C. overa 30 minute period and then to 5-10° C. in an ice bath. The slurry wasstirred for 1 hour at 5-10° C., filtered, and the product was washedwith cold methanol (319 mL, 1.45 mL/g C(3)-acetoxy naltrexone assuming212.5 g naltrexone methobromide (85% overall yield)) to afford 236.1 gof a white solid. The crude product was analyzed by HPLC. This examplewas repeated two additional times and the results are summarized inTable 4. The HPLC assay data for the solid product is an average of twoseparate injections.

TABLE 4 Summary of Results: Example 6 - Synthesis of NaltrexoneMethobromide. 3- Hydrolysis AcNal^(a) Time NalMeD^(a) NalMe^(a) Nal^(a)Yield Run (moles) (hours) (wt. %) (wt. %) (wt. %) (mole %) 1 0.3915 251.47 86.54 0.49 87.2 2 0.4890 17 1.39 86.73 0.60 85.6 3 0.5729 5 1.2587.98 0.57 83.1 ^(a)3-AcNal = C(3)-Acetoxy Naltrexone, NalMeD =Naltrexone Methobromide Diastereomer, NalMe = Naltrexone Methobromide,Nal = Naltrexone Base.

Example 7 Recrystallization of Naltrexone Methobromide

A mixture of water (15.82 mL, 1.58 mL water/g naltrexone methobromide)and methanol (33.47 mL, 3.35 mL methanol/g naltrexone methobromide) weremixed and heated under a nitrogen atmosphere in a 100 mL three-neckedround bottomed flask equipped with a glass stirring shaft, mechanicalstirrer, reflux condenser, and thermocouple to 60° C., and solidnaltrexone methobromide (10.00 g, 22.92 mmoles) was added. After 15minutes, the solid dissolved and aqueous HBr (0.93 g of a 48% solution,5.5 mmoles, 24 mol %) was added to obtain an aqueous methanol mixturecomprised of 1.63 mL water/g naltrexone methobromide and 3.52 mLmethanol/g naltrexone methobromide. The heating mantle was removed andthe mixture was allowed to slowly cool to room temperature.Crystallization was observed at 48° C. The mixture was cooled to 25° C.over a period of 1 hour, then cooled to 5-10° C. in an ice bath, stirredfor 2 hours, filtered, and the solid was washed with cold methanol (15mL, 1.5 mL/g naltrexone methobromide). The solid was then dried on theBüchner funnel for 15 minutes to afford 10.84 g of naltrexonemethobromide as a white solid contaminated with methanol. The productwas analyzed by HPLC. The HPLC assay data for the solid product is anaverage of two separate injections. The results of several experimentsare summarized in Table 5.

TABLE 5 Summary of Results: Example 7 - Naltrexone MethobromideRecrystallization HBr Water Methanol NalMeD^(a) NalMe^(a) Nal^(a)3-MeNalMe^(a) Recovery Run (mol %) (mL/g NalMe^(a)) (mL/g NalMe) (wt. %)(wt. %) (wt. %) (wt. %) (mole %) 1 12.0 1.81 3.52 0.30 93.53 0.08 0.0787.4 2 18.0 1.72 3.71 0.35 86.45 0.12 0.06 95.4 3 24.0 1.81 3.89 0.3694.21 0.14 0.08 87.0 4 12.0 1.63 3.52 0.37 85.32 0.14 0.06 93.3 5 18.01.72 3.71 0.31 93.45 0.12 0.07 88.3 6 12.0 1.81 3.89 0.31 80.92 0.120.06 91.1 7 24.0 1.81 3.52 0.32 93.59 0.12 0.08 87.7 8 24.0 1.63 3.520.40 90.23 0.15 0.07 96.0 9 12.0 1.63 3.89 0.31 91.10 0.12 0.07 84.9 1024.0 1.63 3.89 0.31 88.81 0.12 0.06 92.8 ^(a)NalMeD = NaltrexoneMethobromide Diastereomer, NalMe = Naltrexone Methobromide, Nal =Naltrexone Base, 3-MeNalMe = C(3)-Methoxy Naltrexone Methobromide.

Example 8 Preparation of Methylnaltrexone Bromide

Methylnaltrexone bromide (R-MNTX). To a mixture of naltrexone base (110Kg@100.0%, 323 moles) and USP Purified water (330 Kg, 3.00 Kg/Kgnaltrexone base, 87 gal, 0.79 gal/Kg naltrexone base) was added 50% NaOH(25.7 Kg, 0.234 Kg/Kg naltrexone base). Toluene (288 Kg, 2.62 Kg/Kgnaltrexone base) was added to the aqueous layer. The mixture was stirredand acetic anhydride (37.8 Kg, 0.344 kg/kg naltrexone base) was added.The resulting mixture was then stirred and the pH was adjusted to9.5-10.5 with 50% NaOH (7.59 Kg, 0.069 Kg/Kg naltrexone base). Aceticanhydride (36.7 Kg, 0.030 Kg/Kg naltrexone base) was added and themixture was stirred and the pH was adjusted to 9.5-10.5 with 50% NaOH(5.06 Kg, 0.046 Kg/Kg naltrexone base). The mixture was allowed tosettle and the layers were separated. The aqueous layer was extractedwith toluene (45.5 Kg, 0.414 Kg/Kg naltrexone base) and the layers wereseparated. The organic layers were combined and the aqueous layer wasdiscarded. A pH 9.0, 0.375 M phosphate buffer solution (165 Kg, 1.5Kg/Kg naltrexone base) was prepared by mixing 5.80 Kg of 85% H₃PO₄(0.0527 Kg/Kg naltrexone base), 9.39 Kg 50% NaOH (0.0854 Kg/Kgnaltrexone base), and 150 Kg DI water (1.36 Kg/Kg naltrexone base). Thecombined toluene layers were then washed with the pH 9.0 phosphatebuffer (165 Kg, 1.5 Kg/Kg naltrexone base). The layers were separatedand the toluene layer was concentrated. The vacuum was broken withnitrogen and acetic anhydride (330 g, 0.003 Kg/Kg naltrexone base) wasadded. The mixture was stirred at 50-55° C. Vacuum was again applied andremaining toluene was removed by distillation. The vacuum was brokenwith nitrogen and 1-methyl-2-pyrrolidinone (268 Kg, 2.44 Kg/Kgnaltrexone base) was added. The mixture was stirred for 60 minutes andcooled to room temperature to afford a solution of 3-acetylnaltrexone inNMP. Methyl bromide (61.2 Kg, 0.556 Kg/Kg naltrexone base) was thenadded with vigorous stirring. The reaction mixture was stirred at 60-65°C. to afford a solution. Reaction completion was ascertained via HPLCanalysis. A 33% HBr/HOAc (w/w) solution (19.8 Kg, 0.180 Kg/Kg naltrexonebase) was added. The mixture was stirred at ˜60° C. Aqueous 48% HBr(54.3 Kg, 0.494 Kg/Kg naltrexone base) was added at 60° C. The mixturewas then stirred at −80° C. and cooled to −55° C. Methanol (288 Kg, 2.62Kg/Kg naltrexone base) was added at ˜55° C. and the slurry was cooled to10° C., stirred at 5-10° C., filtered, and the product was washed withmethanol (220 Kg, 2.0 Kg/Kg naltrexone base) to afford a white,crystalline solid. The purity of the crude methylnaltrexone bromideproduct was ascertained by an HPLC assay method and subsequent rawmaterial charges for recrystallization were calculated employing theweight of the product on a 100% basis.

To a mixture of water (1.58 Kg/Kg methylnaltrexone bromide@100%) andmethanol (2.78 Kg/Kg methylnaltrexone bromide@100%) was added crudemethylnaltrexone bromide. The mixture was heated to 60-65° C. under anitrogen atmosphere and a solution resulted. The solution was filteredand aqueous 48% HBr (0.094 kg/kg methylnaltrexone bromide@100%) wasadded. The mixture was cooled to 10° C., filtered, and the solid waswashed with methanol (1.2 Kg/Kg methylnaltrexone bromide@100%). Theproduct was dried at 70-75° C. to afford 100 Kg of a white crystallinesolid.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As various changes could be made in the above methods and processeswithout departing from the scope of the invention, it is intended thatall matter contained in the above descriptions shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A process for the preparation of a C(3)-O-protected quaternary morphinan alkaloid, the process comprising (i) generating a C(3)-O-protected tertiary morphinan alkaloid by reacting a C(3)-OH tertiary morphinan alkaloid with a protecting group precursor in a biphasic solvent system comprising water and a water immiscible solvent, (ii) isolating the C(3)-O-protected tertiary morphinan alkaloid, (iii) combining the C(3)-O-protected tertiary morphinan alkaloid with an alkylating agent in an anhydrous solvent system to form a reaction product mixture containing the C(3)-O-protected quaternary morphinan alkaloid and any unreacted C(3)-O-protected tertiary morphinan alkaloid, the anhydrous solvent system comprising an anhydrous aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt. % of the anhydrous solvent system, and (iv) adding a non-solubilizing solvent to the reaction product mixture to precipitate the C(3)-O-protected quaternary morphinan alkaloid, wherein the C(3)-OH tertiary morphinan alkaloid has the structure of Formula 11, the C(3)-O-protected tertiary morphinan alkaloid substrate has the structure of Formula 111 and the C(3)-O-protected quaternary morphinan alkaloid has the structure of Formula 111A:

wherein A is —C(O)—, —C(S)—, —C(═CH₂)—, —CH(A₁)- or —C(A₁)=, A₁ is hydroxy, alkoxy, or acyloxy, PG is a hydroxy protecting group; R¹ is hydrocarbyl or substituted hydrocarbyl, R² is hydrocarbyl or substituted hydrocarbyl, X⁻ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate; Y, if present, is hydrogen, hydroxy, alkoxy, or acyloxy, and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and
 14. 2. The process of claim 1, wherein PG comprises methyl, ethyl, propargyl benzyl, acetyl, trityl, silyl, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, trityl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl; and the protection reaction is carried out in the presence of a base comprising sodium bicarbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium bicarbonate, or pyridine.
 3. The process of claim 1, further comprising removing the protecting group from the C(3)-O-protected quaternary morphinan alkaloid of Formula 111A to yield a C(3)-OH quaternary morphinan alkaloid of Formula 111B:


4. A process for the preparation of a C(3)-OH quaternary morphinan alkaloid, the process comprising the steps of: (i) generating a C(3)-O-protected tertiary morphinan alkaloid corresponding to Formula 111 by reacting a C(3)-OH tertiary morphinan alkaloid corresponding to Formula 11 with a protecting group precursor in a biphasic solvent system comprising water and a water immiscible solvent; (ii) isolating the generated C(3)-O-protected tertiary morphinan alkaloid; (iii) combining the isolated C(3)-O-protected tertiary morphinan alkaloid with an alkylating agent in an anhydrous solvent system to form a reaction product mixture, the reaction product mixture containing a C(3)-O-protected quaternary morphinan alkaloid and any unreacted C(3)-O-protected tertiary morphinan alkaloid in the anhydrous solvent system, the anhydrous solvent system comprising an aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt. % of the solvent system, the C(3)-O-protected quaternary morphinan alkaloid corresponding to Formula 111A; (iv) adding a non-solubilizing solvent to the reaction product mixture to precipitate and isolate the C(3)-O-protected quaternary morphinan alkaloid from the reaction product mixture and; (v) removing the protecting group from the isolated C(3)-O-protected quaternary morphinan alkaloid to yield the C(3)-OH quaternary morphinan alkaloid corresponding to Formula 111B; wherein Formulae 11, 111, 111A, and 111B have the following structures:

wherein A is —C(O)—, —C(S)—, —C(═CH₂)—, —CH(A₁)- or —C(A₁)=, A₁ is hydroxy, alkoxy, or acyloxy, PG is a hydroxy protecting group, R¹ is hydrocarbyl or substituted hydrocarbyl, R² is hydrocarbyl or substituted hydrocarbyl, X⁻ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate: Y, if present, is hydrogen, hydroxy, alkoxy, or acyloxy, and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and
 14. 5. The process of claim 4, wherein PG is methyl, ethyl, propargyl, benzyl, acetyl, trityl, silyl, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (8-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, trityl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
 6. A process for the preparation of a C(3)-OH quaternary morphinan alkaloid, the process comprising: (i) forming a C(3)-O-protected tertiary morphinan alkaloid, comprising: (A) treating a C(3)-OH tertiary morphinan alkaloid with a protecting group precursor in a biphasic first solvent system comprising water and a water immiscible solvent to form a first reaction product mixture comprising the C(3)-O-protected tertiary morphinan alkaloid and the water immiscible solvent in an organic layer, and the protecting group precursor, the C(3)-OH tertiary morphinan alkaloid, and water in an aqueous layer; (B) separating the organic layer from the aqueous layer; (C) drying the organic layer; (D) treating the dried organic layer produced in step (i)(C) with additional protecting group precursor to increase the conversion of the C(3)-OH tertiary morphinan alkaloid to the C(3)-O-protected tertiary morphinan alkaloid; (E) removing water immiscible solvent from the treated organic layer produced in step (i)(D) to form a concentrate comprising the C(3)-O-protected tertiary morphinan alkaloid; and (F) dissolving the concentrate produced in step (i)(E) comprising the C(3)-O-protected tertiary morphinan alkaloid in an anhydrous solvent system; (ii) treating the C(3)-O-protected tertiary morphinan alkaloid in the anhydrous solvent system of step (i)(F) with an alkylating agent to form a second reaction product mixture comprising a C(3)-O-protected quaternary morphinan alkaloid; and (iii) deprotecting the C(3)-O-protected quaternary morphinan alkaloid to form a third reaction product mixture comprising the C(3)-OH quaternary morphinan alkaloid, wherein the C(3)-OH tertiary morphinan alkaloid has the structure of Formula 11, the C(3)-O-protected tertiary morphinan alkaloid has the structure of Formula 111, the C(3)-O-protected quaternary morphinan alkaloid has the structure of Formula 111A, and the C(3)-OH quaternary morphinan alkaloid has the structure of Formula 111B:

wherein A is —C(O)—, —C(S)—, —C(═CH₂)—, —CH(A₁)- or —C(A)=, A₁ is hydroxy, alkoxy, or acyloxy, PG is a hydroxy protecting group, R¹ ishydrocarbyl or substituted hydrocarbyl, R² is hydrocarbyl or substituted hydrocarbyl, X⁻ is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate; Y, if present, is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy, and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and
 14. 7. The process of claim 6, further comprising treating the second reaction product mixture with a purge agent to remove unreacted alkylating agent from the second reaction product mixture prior to deprotecting in step (iii).
 8. The process of claim 6, further comprising washing the organic layer of step (i)(B) with a buffer to remove the unreacted protecting group precursor from the first reaction product mixture prior to reducing the water content of the organic layer in step (i)(C).
 9. The process of claim 6, wherein the third reaction product mixture includes no more than about 0.1% of a C(3)-O-alkyl quaternary or tertiary morphinan alkaloid impurity, relative to the total alkaloid content of the third product mixture.
 10. The process of claim 9, wherein the alkylating agent is methyl bromide, cyclopropylmethyl bromide, dimethyl sulfate, di(cyclopropylmethyl)sulfate, methyl fluorosulfonate, trimethyloxonium fluoroborate, trimethyloxonium hexachloroantimonate, trimethyloxonium hexafluorophosphate, or methyl trifluoromethane sulfonate.
 11. The process of claim 6, wherein the alkylating agent is methyl bromide; the water immiscible solvent is toluene; and the anhydrous solvent system comprises 1-methyl-2-pyrrolidinone.
 12. The process of claim 6, wherein the C(3)-OH tertiary morphinan alkaloid is naltrexone ((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one), oxymorphone ((5α)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one), hydromorphone ((5α)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one), naloxone ((5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one), nalmefene ((5α)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol), nalbuphine ((5α)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol), or oripavine ((5α)-6,7,8,14-tetrahydro-4,5-epoxy-6-methoxy-17-methylmorphinan-3-ol); step (ii) is carried out at a pressure of less than 1.25 atmospheres; Y and Z are independently=OCH₃, —OAc, =OTHP, ═OSiR₃, —OBn, —OBz, —OBs, —OTs, or —OMs wherein each R is independently hydrocarbyl; the anhydrous solvent system contains less than 0.05 wt. % water; and step (ii) is carried out within a temperature range of 55-85° C.
 13. The process of claim 12, wherein PG is acetyl.
 14. The process of claim 6, wherein the protection of step (i)(A) is carried out with acetic anhydride in a water/toluene mixture and sodium hydroxide.
 15. The process of claim 6, wherein the C(3)-OH tertiary morphinan alkaloid is naltrexone or oxymorphone.
 16. A composition comprising R-naltrexone methobromide, S-naltrexone methobromide, the C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, and oxymorphone wherein the composition contains at least 70% (w/w) of S-naltrexone methobromide, at least 1% (w/w) of R-naltrexone methobromide, but no more than 0.2% (w/w) of the C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, based upon the combined weight of the R-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, and oxymorphone in the composition. 